Substituted 1, 4-thiazepine and analogs as activators of caspases and inducers of apoptosis and the use thereof

ABSTRACT

The present invention is directed to substituted 1,4-thiazepine and analogs thereof, represented by the general Formula I: 
                 
 
wherein the dashed lines, A 1 , A 2 , A 3 , X 1  and R 1  are defined herein. The present invention also relates to the discovery that compounds having Formula I are activators of capases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention can be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. § 119 (e)1 of priorfiled U.S. Provisional Application No. 60/197,599, filed on Apr. 18,2000, the contents of which are entirely incorporated by referenceherein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of medicinal chemistry. In particular,the invention relates to substituted 1,4-thiazepine and analogs, and thediscovery that these compounds are activators of caspases and inducersof apoptosis. The invention also relates to the use of these compoundsas therapeutically effective anti-cancer agents.

2. Related Art

Organisms eliminate unwanted cells by a process variously known asregulated cell death, programmed cell death or apoptosis. Such celldeath occurs as a normal aspect of animal development as well as intissue homeostasis and aging (Glucksmann, A., Biol. Rev. CambridgePhilos. Soc. 26:59-86 (1951); Glucksmann, A., Archives de Biologie76:419-437 (1965); Ellis, et al., Dev. 112:591-603 (1991); Vaux, et al.Cell 76:777-779 (1994)). Apoptosis regulates cell number, facilitatesmorphogenesis, removes harmful or otherwise abnormal cells andeliminates cells that have already performed their function.Additionally, apoptosis occurs in response to various physiologicalstresses, such as hypoxia or ischemia (PCT published applicationWO96/20721).

There are a number of morphological changes shared by cells experiencingregulated cell death, including plasma and nuclear membrane blebbing,cell shrinkage (condensation of nucleoplasm and cytoplasm), organellerelocalization and compaction, chromatin condensation and production ofapoptotic bodies (membrane enclosed particles containing intracellularmaterial) (Orrenius, S., J. Internal Medicine 237:529-536 (1995).

Apoptosis is achieved through an endogenous mechanism of cellularsuicide (Wyllie, A. H., in Cell Death in Biology and Pathology, Bowenand Lockshin, eds., Chapman and Hall (1991), pp. 9-34). A cell activatesits internally encoded suicide program as a result of either internal orexternal signals. The suicide program is executed through the activationof a carefully regulated genetic program (Wyllie, et al., Int Rev. Cyt.68:251 (1980); Ellis, et al., Ann Rev. Cell Bio. 7:663 (1991). Apoptoticcells and bodies are usually recognized and cleared by neighboring cellsor macrophages before lysis. Because of this clearance mechanism,inflammation is not induced despite the clearance of great numbers ofcells (Orrenius, S., J Internal Medicine 237:529-536(1995)).

A group of proteases are a key element in apoptosis (see, e.g.,Thorneberry, Chemistry and Biology 5:R97-R103 (1998); Thornberry,British Med. Bull. 53:478-490 (1996)). Genetic studies in the nematodeCaenorhabditis elegans revealed that apoptotic cell death involves atleast 14 genes, two of which are the pro-apoptotic (death-promoting) ced(for cell death abnormal) genes, ced-3 and ced-4. CED-3 is homologous tointerleukin 1 beta-converting enzyme, a cysteine protease, which is nowcalled caspase-1. Further extensive research revealed that the mammalianapoptosis system appears to involve a cascade of caspases, or a systemthat behaves like a cascade of caspases. At present, the caspase familyof cysteine proteases comprises 14 different members, and more may bediscovered in the future. All known caspases are synthesized as zymogensthat require cleavage at an aspartyl residue prior to forming the activeenzyme. Thus, caspases are capable of activating other caspases in themanner of an amplifying cascade.

Apoptosis and caspases are thought to be crucial in the development ofcancer (Apoptosis and Cancer Chemotherapy, Hickman and Dive, eds.,Humana Press (1999)). There is mounting evidence that cancer cells,while containing caspases, lack parts of the molecular machinery thatactivate the caspase cascade. This makes the cancer cells lose theircapacity to undergo cellular suicide and the cells become immortal,i.e., they become cancerous. Control points are known to exist in theapoptosis process that represent points for intervention leading toactivation. These control points include the CED-9-BCL-like andCED-3-ICE-like gene family products, which are intrinsic proteinsregulating the fate of a cell to survive or die, respectively, andexecuting part of the cell death process itself (see, Schmitt, et al.,Biochem. Cell. Biol. 75:301-314 (1997)). BCL-like proteins includeBCL-XL and BAX-alpha, which appear to function upstream of caspaseactivation. BCL-xL appears to prevent activation of the apoptoticprotease cascade, whereas BAX-alpha accelerates activation of theapoptotic protease cascade.

Chemotherapeutic (anti-cancer) drugs can trigger cancer cells to undergosuicide by activation of the dormant caspase cascade. This may be acrucial aspect of the mode of action of most, if not all, knownanticancer drugs (Los, et al., Blood 90:3118-3129 (1997); Friesen, etal., Nat. Med. 2:574 (1996)). The mechanism of action of currentantineoplastic drugs frequently involves an attack at specific phases ofthe cell cycle. The cell cycle refers to the stages through which cellsnormally progress during their lifetimes. Normally, cells exist in aresting phase termed G₀. During multiplication, cells progress to astage in which DNA synthesis occurs, termed S. Later, cell division, ormitosis, occurs in a phase called M. Antineoplastic drugs such ascytosine arabinoside, hydroxyurea, 6-mercaptopurine, and methotrexateare S phase specific, whereas antineoplastic drugs such as vincristine,vinblastine, and paclitaxel are M phase specific. Many slow growingtumors, for example colon cancers, exist primarily in the G₀ phase,whereas rapidly proliferating normal tissues, for example bone marrow,exist primarily in the S or M phase. Thus, the possibility exists forthe activation of the caspase cascade, although the exact mechanisms fordoing so presently are not clear. Furthermore, insufficient activity ofthe caspase cascade and consequent apoptotic events are implicated invarious types of cancer. The development of caspase cascade activatorsand inducers of apoptosis is a highly desirable goal in the developmentof therapeutically effective antineoplastic agents. Moreover, sinceautoimmune disease and certain degenerative diseases also involve theproliferation of abnormal cells, therapeutic treatment for thesediseases could be effected by enhancement of the apoptotic processthrough the administration of appropriate caspase cascade activators andinducers of apoptosis.

Sucheta et al., (Indian J. Chem. Sect. B: 34B:893-4 (1995)) reported thesynthesis of 1,4-benzothiazepine derivatives by reaction of2-aminothiophenol with 3-cinnamoyl-2-pyrones (R=2-OMe, 2-, 4-OH, 2-,4-NO₂, 2,6-Cl₂, 2-Cl):

SUMMARY OF THE INVENTION

The present invention is related to novel compounds of Formula I and theuse of such compounds for treating, preventing or ameliorating neoplasiaand cancer.

A second aspect of the present invention is related to the discoverythat substituted 1,4-thiazepine and analogs are activators of thecaspase cascade and inducers of apoptosis. Thus, an aspect of thepresent invention is directed to substituted 1,4-thiazepine and analogsas inducers of apoptosis.

A third aspect of the present invention is to provide a method fortreating, preventing or ameliorating neoplasia and cancer byadministering a compound of Formula I to a mammal in need of suchtreatment.

A fourth aspect of the present invention is to provide a pharmaceuticalcomposition useful for treating disorders responsive to the induction ofapoptosis, containing an effective amount of a compound of Formula I inadmixture with one or more pharmaceutically acceptable carriers ordiluents.

A fifth aspect of the present invention is directed to methods for thepreparation of compounds of Formula I.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention arises out of the discovery that substituted1,4-thiazepine and analogs, as represented in Formula I, are potent andhighly efficacious activators of the caspase cascade and inducers ofapoptosis. Therefore compounds of Formula I are useful for treatingdisorders responsive to induction of apoptosis.

Specifically, compounds useful in this aspect of the present inventionare represented by Formula I:

in which:

-   -   the dashed lines indicate optional unsaturation without        violating valency rules;    -   R¹ is hydrogen, (C₁₋₆)alkyl or —C(O)R⁶, wherein R⁶ is as defined        below, or R¹ is absent when a double bond exists between the        nitrogen atom to which R¹ is attached and an adjacent ring atom        or R¹ is as defined below;    -   X¹ is —NR²—, —S—, —S(O)—, —S(O)₂— or —O—, wherein R² is hydrogen        or (C₁₋₆)alkyl or is absent when a double bond exists between        the nitrogen atom to which R² is attached and an adjacent ring        atom;    -   A¹ is a monocyclic or fused polycyclic ring system selected from        aryl containing a total of 6 to 14 ring atoms, heteroaryl        containing a total of 5 to 14 ring atoms and unsaturated,        partially unsaturated or saturated carbocycloalkyl or        heterocycloalkyl each containing a total of 3 to 14 ring atoms,        or A¹ together with R¹ and the atoms to which A¹ and R¹ are        attached forms a fused polycyclic ring system selected from        heteroaryl and unsaturated, partially unsaturated or saturated        heterocycloalkyl in any case containing a total of 10 to 15 ring        atoms, wherein A¹ may be substituted with a group selected from        —X²R³, —X²OR³, —X²C(O)R³, —X²OC(O)R³, —X²C(O)OR³, —X²SR³,        —X²S(O)R³, —X²S(O)₂R³, —X^(2NR) ³R⁴, —X²NR⁴C(O)R³,        —X²NR⁴C(O)OR³, —X²C(O)NR³R⁴, —X²NR⁴C(O)NR³R⁴, —X²NR⁴C(NR⁴)NR³R⁴,        —X²NR⁴S(O)₂R³ and —X²S(O)₂NR³R⁴, wherein X² is a bond or        (C₁₋₆)alkylene, R³ is —X²R⁵ wherein X² is as defined above and        R⁵ is aryl containing a total of 6 to 10 ring atoms, heteroaryl        containing a total of 5 to 10 ring atoms or unsaturated,        partially unsaturated or saturated carbocycloalkyl or        heterocycloalkyl each containing a total of 3 to 10 ring atoms,        and R⁴ at each occurrence independently is hydrogen, (C₁₋₆)alkyl        or halo-substituted (C₁₋₆)alkyl, wherein each ring within A¹ and        R⁵ contains from 3 to 8 ring atoms and may be substituted with 1        to 3 groups independently selected from (C₁₋₆)alkyl, cyano,        halo, nitro, halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶,        —X²OC(O)R⁶, —X²C(O)OR⁴, —X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴,        —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴, —X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴,        —X²NR⁴C(NR⁴)NR⁴R⁴, —X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴, wherein X²        and R⁴ are as defined above and R⁶ is (C₁₋₆)alkyl or        halo-substituted (C₁₋₆)alkyl, and wherein any said        carbocycloalkyl and heterocycloalkyl rings within A¹ and R⁵ may        be substituted further with 1 to 2 groups independently selected        from (C₁₋₆)alkylidene, oxo, imino and thioxo, with the proviso        that only one of A¹ and R⁵ is a fused polycyclic ring system;    -   A² is a monocyclic or fused bicyclic ring selected from        heteroarylene or unsaturated, partially unsaturated or saturated        heterocycloalkylene containing a total of 5 to 11 ring atoms,        wherein A² may be substituted with a group selected from —X²R⁸,        —X²OR⁸, —X²C(O)R⁸, —X²OC(O)R⁸, —X²C(O)OR⁸, —X²SR⁸, —X²S(O)R⁸,        —X²S(O)₂R⁸, —X²NR⁴R⁸, —X²NR⁴C(O)R⁸, —X²NR⁴C(O)OR⁸, —X²C(O)NR⁴R⁸,        —X²NR⁴C(O)NR⁴R⁸, —X²NR⁴C(NR⁴)NR⁴R⁸, —X²NR⁴S(O)₂R⁸ and        —X²S(O)₂NR⁴R⁸, wherein X² is a bond or (C₁₋₆)alkylene, R⁸ is        —X²R⁹ wherein X² is as defined above and R⁹ is aryl containing a        total of 6 to 10 ring atoms, heteroaryl containing a total of 5        to 10 ring atoms or unsaturated, partially unsaturated or        saturated carbocycloalkyl or heterocycloalkyl each containing a        total of 3 to 10 ring atoms, and R⁴ at each occurrence        independently is hydrogen, (C₁₋₆)alkyl or halo-substituted        (C₁₋₆)alkyl, wherein each ring within A² and R⁸ contains from 3        to 8 ring atoms and may be substituted with 1 to 3 groups        independently selected from (C₁₋₆)alkyl, cyano, halo, nitro,        halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶,        —X²C(O)OR⁴, —X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴,        —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴, —X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴,        —X²NR⁴C(NR⁴)NR⁴R⁴, —X²C(O)NR⁴X²C(O)OR⁴, —X²NR⁴S(O)₂R⁶ and        —X²S(O)₂NR⁴R⁴, wherein X² and R⁴ are as defined above and R⁶ is        (C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl, and wherein any        said heterocycloalkylene, carbocycloalkyl and heterocycloalkyl        rings within A² and R⁸ may be substituted further with 1 to 2        groups independently selected from (C₁₋₆)alkylidene, oxo, imino        and thioxo, with the proviso that only one of A² and R⁸ is a        fused polycyclic ring system; and    -   A³ is a monocyclic or fused polycyclic ring system selected from        aryl containing a total of 6 to 14 ring atoms, heteroaryl        containing a total of 5 to 14 ring atoms and unsaturated,        partially unsaturated or saturated carbocycloalkyl or        heterocycloalkyl each containing a total of 3 to 14 ring atoms,        wherein A³ may be substituted with a group selected from —X²R⁹,        —X²OR⁹, —X²C(O)R⁹, —X²OC(O)R⁹, —X²C(O)OR⁹, —X²SR⁹, —X²S(O)R⁹,        —X²S(O)₂R⁹, —X²NR⁴R⁹, —X²NR⁴C(O)R⁹, —X²NR⁴C(O)OR⁹, —X²C(O)NR⁴R⁹,        —X²NR⁴C(O)NR⁴R⁹, —X²NR⁴C(NR⁴)NR⁴R⁹, —X²NR⁴S(O)₂R⁹ and        —X²S(O)₂NR⁴R⁹, wherein X² is a bond or (C₁₋₆)alkylene, R⁹ is        —X²R¹⁰ wherein X² is as defined above and R¹⁰ is aryl containing        a total of 6 to 10 ring atoms, heteroaryl containing a total of        5 to 10 ring atoms or unsaturated, partially unsaturated or        saturated carbocycloalkyl or heterocycloalkyl each containing a        total of 3 to 10 ring atoms, and R⁴ at each occurrence        independently is hydrogen, (C₁₋₆)alkyl or halo-substituted        (C₁₋₆)alkyl, wherein each ring within A³ and R¹⁰ contains from 3        to 8 ring atoms and may be substituted with 1 to 3 groups        independently selected from (C₁₋₆)alkyl, cyano, halo, nitro,        halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶,        —X²C(O)OR⁴, —X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴,        —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴, —X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴,        —X²NR⁴C(NR⁴)NR⁴R⁴, —X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴, wherein X²        and R⁴ are as defined above and R⁶ is (C₁₋₆)alkyl or        halo-substituted (C₁₋₆)alkyl, and wherein any said        carbocycloalkyl and heterocycloalkyl rings within A³ and R¹⁰ may        be substituted further with 1 to 2 groups independently selected        from (C₁₋₆)alkylidene, oxo, imino and thioxo, with the proviso        that only one of A³ and R¹⁰ is a fused polycyclic ring system;        and the N-oxide derivatives, prodrug derivatives, protected        derivatives, individual stereoisomers and mixtures of        stereoisomers; and the pharmaceutically acceptable salts        thereof;        with the proviso that when said compound is selected from the        group consisting of Formulae II(a), II(b) and II(c):        then A³ is other than:    -   unsubstituted pyridyl;    -   unsubstituted thienyl;    -   unsubstituted indolyl;    -   unsubstituted phenyl;    -   benzo[1,3]dioxolyl;    -   2,3-dihydro-benzo[1,4]dioxinyl;    -   phenyl which is mono-substituted by fluoro, bromo, iodo, methyl,        isopropyl, ethoxy or methylsulfanyl; and    -   phenyl which is substituted by at least one of chloro, hydroxy        or methoxy. Alternatively, compounds useful for treating        disorders responsive to induction of apoptosis are represented        by Formula II:        in which:    -   the dashed lines indicate optional unsaturation without        violating valency rules;    -   R¹ is hydrogen, (C₁₋₆)alkyl or —C(O)R⁶, wherein R⁶ is asdefined        below, or is absent when a double bond exists between the        nitrogen atom to which R¹ is attached and an adjacent ring atom        or R¹ is as defined below;    -   R⁷ is hydrogen;    -   X¹ is —NR²—, —S—, —S(O)—, —S(O)₂— or —O—, wherein R² is hydrogen        or (C₁₋₆)alkyl or is absent when a double bond exists between        the nitrogen atom to which R² is attached and an adjacent ring        atom;    -   A² is a monocyclic or fused bicyclic ring selected from        heteroarylene or unsaturated, partially unsaturated or saturated        heterocycloalkylene containing a total of 5 to 11 ring atoms,        wherein A² may be substituted with a group selected from —R⁸,        —X²OR⁸, —X²C(O)R⁸, —X²OC(O)R⁸, —X²C(O)OR⁸, —X²SR⁸, —X²S(O)R⁸,        —X²S(O)₂R⁸, —X²NR⁴R⁸, —X²NR⁴C(O)R⁸, —X²NR⁴C(O)OR⁸, —X²C(O)NR⁴R⁸,        —X²NR⁴C(O)NR⁴R⁸, —X²NR⁴C(NR⁴)NR⁴R⁸, —X²NR⁴S(O)₂R⁸ and        —X²S(O)²NR⁴R⁸, wherein X² is a bond or (C₁₋₆)alkylene, R⁸ is        —X²R⁹ wherein X² is as defined above and R⁹ is aryl containing a        total of 6 to 10 ring atoms, heteroaryl containing a total of 5        to 10 ring atoms or unsaturated, partially unsaturated or        saturated carbocycloalkyl or heterocycloalkyl each containing a        total of 3 to 10 ring atoms, and R⁴ at each occurrence        independently is hydrogen, (C₁₋₆)alkyl or halo-substituted        (C₁₋₆)alkyl, wherein each ring within A² and R⁸ contains from 3        to 8 ring atoms and may be substituted with 1 to 3 groups        independently selected from (C₁₋₆)alkyl, cyano, halo, nitro,        halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶,        —X²C(O)OR⁴, —X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴,        —X²NR⁴C(O)R⁶, —X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴, —X²NR⁴C(NR)⁴)NR⁴R⁴,        —X²C(O)NR⁴X²C(O)OR⁴, —X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴, wherein X²        and R⁴ are as defined above and R⁶ is (C₁₋₆)alkyl or        halo-substituted (C₁₋₆)alkyl, and wherein any said        heteroalkylene, carbocycloalkyl and heterocycloalkyl rings        within A² and R⁸ may be substituted further with 1 to 2 groups        independently selected from (C₁₋₆)alkylidene, oxo, imino and        thioxo with the proviso that only one of A² and R⁸ is a fused        polycyclic ring system; and    -   A³ is a monocyclic or fused polycyclic ring system selected from        aryl containing a total of 6 to 14 ring atoms, heteroaryl        containing a total of 5 to 14 ring atoms and unsaturated,        partially unsaturated or saturated carbocycloalkyl or        heterocycloalkyl each containing a total of 3 to 14 ring atoms,        wherein A³ may be substituted with a group selected from —R⁹,        —X²OR⁹, —X²C(O)R⁹, —X²OC(O)R⁹, —X²C(O)OR⁹, —X²SR⁹, —X²S(O)R⁹,        —X²S(O)₂R⁹, —X²NR⁴R⁹, —X²NR⁴C(O)R⁹, —X²NR⁴C(O)OR⁹, —X²C(O)NR⁴R⁹,        —X²NR⁴C(O)NR⁴R⁹, —X²NR⁴C(NR⁴)NR⁴R⁹, —X²NR⁴S(O)₂R⁹ and        —X²S(O)₂NR⁴R⁹, wherein X² is a bond or (C₁₋₆)alkylene, R⁹ is        —X²R¹⁰ wherein X² is as defined above and R¹⁰ is aryl containing        a total of 6 to 10 ring atoms, heteroaryl containing a total of        5 to 10 ring atoms or unsaturated, partially unsaturated or        saturated carbocycloalkyl or heterocycloalkyl each containing a        total of 3 to 10 ring atoms, and R⁴ at each occurrence        independently is hydrogen, (C₁₋₆)alkyl or halo-substituted        (C₁₋₆)alkyl, wherein each ring within A³ and R¹⁰ contains from 3        to 8 ring atoms and may be substituted with 1 to 3 groups        independently selected from (C₁₋₆)alkyl, cyano, halo, nitro,        halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶,        —X²C(O)OR⁴, —X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴,        —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴, —X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴,        —X²NR⁴C(NR⁴)NR⁴R⁴, —X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴, wherein X²        and R⁴ are as defined above and R⁶ is (C₁₋₆)alkyl or        halo-substituted (C₁₋₆)alkyl, and wherein any said        carbocycloalkyl and heterocycloalkyl rings within A³ and R¹⁰ may        be substituted further with 1 to 2 groups independently selected        from (C₁₋₆)alkylidene, oxo, imino and thioxo with the proviso        that only one of A³ and R¹⁰ is a fused polycyclic ring system;        and the N-oxide derivatives, prodrug derivatives, protected        derivatives, individual stereoisomers and mixtures of        stereoisomers; and the pharmaceutically acceptable salts        thereof;    -   provided, however, Formula II does not represent a compound        wherein A² is 2,3,6,7-tetrahydro-[1,4]thiazepinylene,        2,3-dihydro-benzo[b][1,4]thiazepinylene or        7-trifluoromethyl-2,3-dihydro-benzo[b][1,4]thiazepinylene when        A³ is benzo[1,3]dioxolyl, indolyl, phenyl, pyridyl or thienyl,        wherein said phenyl may be substituted with 1 to 3 groups        independently selected from halo, nitro, hydroxy, (C₁₋₄)alkyl,        (C₁₋₄)alkylsulfanyl and (C₁₋₄)alkyloxy; or any N-oxide        derivative, protected derivative, individual stereoisomer or        mixture of stereoisomers, or pharmaceutically acceptable salt        thereof.

Preferred are compounds of Formula I in which A³ is other thanunsubstituted pyridyl; unsubstituted thienyl; unsubstituted indolyl;unsubstituted phenyl; benzo[1,3]dioxol-5-yl;2,3-dihydro-benzo[1,4]dioxinyl; orphenyl which is substituted by atleast one of halogen, nitro, hydroxy, (C₁₋₃)alkyl, methoxy, ethoxy andmethylsulfanyl; and more preferred wherein A¹ is other than4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl.

Preferred are compounds of Formula I(A):

wherein R¹, A¹, A² and A³ are as in the Detailed Description of theInvention for Formula I; and more preferred are compounds of FormulaI(B):

wherein A¹, A² and A³ are as in the Detailed Description of theInvention for Formula I; and most preferred are compounds of Formula Iin which A² is that is 2,3,6,7-tetrahydro-[1,4]thiazepin-5,7-ylene, thatis a compound of Formula I(C):

wherein A¹ and A³ are as in the Detailed Description of the Inventionfor Formulaland said 2,3,6,7-tetrahydro-[1,4]thiazepin-5,7-ylene maybesubstituted with 1 to 3 groups independently selected from (C₁₋₆)alkyl,cyano, halo, nitro, halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶,—X²OC(O)R⁶, —X²C(O)OR⁴, —X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴,—X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴, —X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴,—X²NR⁴C(NR⁴)NR⁴R⁴, —X²C(O)NR⁴X²C(O)OR⁴, —X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴,wherein X² is a bond or (C₁₋₆)alkylene, R⁴ at each occurrenceindependently is hydrogen, (C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl,and R⁶ is (C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl.

Preferred are compounds of Formula I(C) in which A¹ is4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; and more preferred wherein saidcompound is selected from the group consisting of:

-   -   4-hydroxy-6-methyl-3-[7-(3-phenyl-1H-pyrazol-4-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   3-[7-(5-ethyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(1-benzyl-1H-indol-3-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   4-hydroxy-6-methyl-3[7-(2-trifluoromethylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   4-hydroxy-6-methyl-3[7-(3-trifluoromethylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   4-hydroxy-6-methyl-3[7-(4-trifluoromethylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   4-hydroxy-6-methyl-3-[7-[3-(3-trifluoromethyl-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   3-[7-[3-(3,4-dichloro-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-[3-(3,5-dichloro-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   4-hydroxy-6-methyl-3-{7-[5-(3-trifluoromethyl-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-pyran-2-one;    -   3-{7-[5-(2-chloro-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;    -   3-{7-[5-(3-chloro-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;    -   3-{7-[5-(4-chloro-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;    -   4-hydroxy-6-methyl-3-{7-[5-(chloro-trifluoromethyl-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-pyran-2-one;    -   3-[7-(4-bromo-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(5-bromo-thien-2-yl)-2,3,6,7-tetrahydro-[ 1        ,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(1-benzenesulfonyl-1H-pyrrol-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   4-hydroxy-6-methyl-3-[7-(3-methyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   4-hydroxy-6-methyl-3-[7-(5-methyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   4-hydroxy-6-methyl-3-[7-(1-methyl-1H-indol-3-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   3-[7-(chloro-methyl-trifluoromethyl-1H-pyrazol-4-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-{7-[1-(2,4-difluoro-benzenesulfonyl)-1H-pyrrrol-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;    -   3-(7-[2,2′]bithienyl-5-yl-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl)-4-hydroxy-6-methyl-pyran-2-one;    -   3-{7-[1-(3,5-dichloro-phenyl)-1H-pyrrrol-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;    -   3-{7-[1-(4-chloro-phenyl)-1H-pyrrrol-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl        }-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(5-chloro-1H-indol-3-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   4-hydroxy-6-methyl-3-[7-(6-p-tolylsulfanyl-imidazo[2,1-b]thiazol-5-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   3-[7-(4,5-dibromo-thien-2-yl)-2,3,6,7-tetrahydro-[ 1        ,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   4-hydroxy-6-methyl-3-[7-(5-methylsulfanyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   3-[7-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(4-dimethylamino-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   4-hydroxy-6-methyl-3-[7-(4-trifluoromethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   3-[7-(bis-trifluoromethyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   4-hydroxy-3-[7-(4-methanesulfonyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one;        and    -   3-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-methoxy-6-methyl-pyran-2-one.

Preferred are compounds of Formula I(C) in which A¹ is A¹ is4-hydroxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl; and more preferredwherein said compound is selected from the group consisting of:

-   -   3-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one;    -   3-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one;    -   3-[7-(4-dimethylamino-phenyl)-2,3,6,7-tetrahydro-1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one;        and    -   3-[7-(2,3,4-trimethoxy-phenyl)-2,3,6,7-tetrahydro-1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one.

Preferred are compounds of Formula I(C) in which A¹ is2-hydroxy-6-oxo-cyclohex-1-enyl or 2-methoxy-6-oxo-cyclohex-1-enyl; andmore preferred wherein said compound is selected from the groupconsisting of:

-   -   2-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-3-hydroxy-cyclohex-2-enone;    -   2-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-3-hydroxy-cyclohex-2-enone;        and    -   3-hydroxy-2-[7-(2,3,4-trimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-cyclohex-2-enone.

Preferred are compounds of Formula I(C) in which A¹ is a group ofFormula (c):

in which R⁷ is hydrogen or methyl, R¹¹ is hydrogen or (C₁₋₆)alkyl andthe free valence is attached to A²; and in particular the compound ofFormula I(C) which is3-[7-2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-1H-quinolin-2-one.

Preferred are compounds of Formula I in which A² is2,3-dihydro-benzo[b][1,4]thiazepin-5,7-ylene, that is a compound ofFormula I(D):

in which A¹ and A³ are defined as in the Detailed Description of theInvention for Formula I, and said2,3-dihydro-benzo[b][1,4]thiazepin-5,7-ylene may be substituted with 1to 3 groups independently selected from (C₁₋₆)alkyl, cyano, halo, nitro,halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶, —X²C(O)OR⁴,—X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴, —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴,—X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴, —X²NR⁴C(NR⁴)NR⁴R⁴, —X²NR⁴S(O)₂R⁶ and—X²S(O)₂NR⁴R⁴, wherein X² is a bond or (C₁₋₆)alkylene, R⁴ at eachoccurrence independently is hydrogen, (C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl, and R⁶ is (C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl.

Preferred are compounds of Formula I(D) in which A¹ is4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; and more preferred wherein saidcompound is3-[2-(2,4-diethoxy-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-4-hydroxy-6-methyl-pyran-2-one.

Preferred are compounds of Formula I(D) in which A¹ is4-hydroxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl; and more preferredwherein said compound is4-hydroxy-6-methyl-3-[2-(2,3,4-trimethoxy-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-5,6-dihydro-pyran-2-one.

Preferred are compounds of Formula I(D) in which A¹ is2-hydroxy-6-oxo-cyclohex-1-enyl or 2-methoxy-6-oxo-cyclohex-1-enyl; andmore preferred wherein said compound is selected from the groupconsisting of:

-   -   3-hydroxy-2-[2-(2,4-diethoxy-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-cyclohex-2-enone;        and    -   3-hydroxy-2-[2-(2,3,4-trimethoxy-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-cyclohex-2-enone.

Preferred are compounds of Formula I in which A² is a group of Formula(k):

in which R¹ is defined as in the Detailed Description of the Inventionfor Formula I and said group of Formula (k) may be substituted with 1 to3 groups independently selected from (C₁₋₆)alkyl, cyano, halo, nitro,halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶, —X²C(O)OR⁴,—X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴, —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴,—X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴, —X²NR⁴C(NR⁴)NR⁴R⁴, —X²C(O)NR⁴X²C(O)OR⁴,—X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴, wherein X² is a bond or (C₁₋₆)alkylene,R⁴ at each occurrence independently is hydrogen, (C₁₋₆)alkyl orhalo-substituted (C₁₋₆)alkyl, and R⁶ is (C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl; preferably wherein R¹ is hydrogen.

Preferred are compounds of Formula I in which in which A² is a group ofFormula (k) and A¹ is 4-hydroxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-ylor 4-methoxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl; and morepreferred wherein said compound is selected from the group consistingof:

-   -   3-[4-acetyl-7-(2,4-dimethoxy-phenyl)-[1,4]thiazepan-5-yl]-4-hydroxy-6-methyl-pyran-2-one;        and    -   3-[7-(2,4-dimethoxy-phenyl)-4-(2,2,2-trifluoro-ethanoyl)-[1,4]thiazepan-5-yl]-4-hydroxy-6-methyl-pyran-2-one.

Preferred are compounds of Formula I in which in which A² is a group ofFormula (k) and A¹ is optionally substituted phenyl; and more preferredwherein said compound is1-[7-(2,4-dimethoxy-phenyl)-5-(3-fluoro-4-methoxyphenyl)-[1,4]thiazepan-4-yl]-ethanone.

Preferred are compounds of Formula I in which A² is2,3-dihydro-[1,4]thiazepin-5,7-ylene, that is the compound of FormulaI(F):

in which A¹ and A³ are defined as in claim 1, and said2,3-dihydro-[1,4]thiazepin-5,7-ylene may be substituted with 1 to 3groups independently selected from (C₁₋₆)alkyl, cyano, halo, nitro,halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶, —X²C(O)OR⁴,—X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴, —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴,—X²C(O)NR⁴R⁴, —X²NR C(O)NR⁴R⁴, —X²NR⁴C(NR⁴)NR⁴R⁴, —X²C(O)NR⁴X²C(O)OR⁴,—X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴, wherein X² is a bond or (C₁₋₆)alkylene,R⁴ at each occurrence independently is hydrogen, (C₁₋₆)alkyl orhalo-substituted (C₁₋₆)alkyl, and R⁶ is (C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl.

Preferred are compounds of Formula I(F) in which A¹ is4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; and more preferred wherein saidcompound is selected from the group consisting of:

-   -   3-[7-(2,4-dimethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(2,4-diethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]4-hydroxy-6-methyl-pyran-2-one;        and    -   3-(7-[2,2′]bithienyl-5-yl-2,3-dihydro-[1,4]thiazepin-5-yl)-4-hydroxy-6-methyl-pyran-2-one.

Preferred are compounds of Formula I(F) in which A¹ is4-hydroxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl; and more preferredwherein said compound is3-[7-(2,4-diethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one.

Preferred are compounds of Formula I(F) in which A¹ is2-hydroxy-6-oxo-cyclohex-1-enyl or 2-methoxy-6-oxo-cyclohex-1-enyl; andmore preferred wherein said compound is2-[7-(2,4-diethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-3-hydroxy-cyclohex-2-enone.

Preferred are compounds of Formula I(G):

wherein n, R¹, A¹ , A² and A³ are as in the Detailed Description of theInvention for Formula I; and more preferred are compounds of FormulaI(G) in which A² is is a group of Formula (1):

wherein n is 1 or 2; and said group of Formula (1) may be substitutedwith 1 to 3 groups independently selected from (C₁₋₆)alkyl, cyano, halo,nitro, halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶,—X²C(O)OR⁴, —X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴, —X²NR⁴C(O)R⁶,—X²NR⁴C(O)OR⁴, —X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴, —X²NR⁴C(NR⁴)NR⁴R⁴,—X²C(O)NR⁴X²C(O)OR⁴, —X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴, wherein X² is abond or (C₁₋₆)alkylene, R⁴ at each occurrence independently is hydrogen,(C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl, and R⁶ is (C₁₋₆)alkyl orhalo-substituted (C₁₋₆)alkyl.

Preferred are compounds of Formula I(G) in which A² is is a group ofFormula (1) wherein n is 1 and A¹ is4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; in particular the compound whichis3-[7-(2,4-dimethoxy-phenyl)-1-oxo-2,3,6,7-tetrahydro-1H-1λ⁴-[1,4]thiazepin-5-yl]-4-hydroxy-6-methoxy-pyran-2-one.

Preferred are compounds of Formula I(G) in which A² is is a group ofFormula (1) wherein n is 2 and A¹ is4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; in particular the compound whichis3-[7-(2,4-dimethoxy-phenyl)-1,1-dioxo-2,3,6,7-tetrahydro-1H-1λ⁶-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one.

Preferred are compounds of Formula I(I):

wherein R¹, R², A¹, A² and A³ are as in the Detailed Description of theInvention for Formula I; and more preferred are compounds of FormulaI(I) in which A² is is a group of Formula (j):

wherein said group of Formula (1) may be substituted with 1 to 3 groupsindependently selected from (C₁₋₆)alkyl, cyano, halo, nitro,halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶, —X²C(O)OR⁴,—X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴, —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴,—X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴, —X²NR⁴C(NR⁴)NR⁴R⁴, —X²C(O)NR⁴X²C(O)OR⁴,—X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴, wherein X² is a bond or (C₁₋₆)alkylene,R⁴ at each occurrence independently is hydrogen, (C₁₋₆)alkyl orhalo-substituted (C₁₋₆)alkyl, and R⁶ is (C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl.

Preferred are compounds of Formula I(I) in which A ² is is a group ofFormula (j) wherein A¹ is 4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; in particular the compound whichis3-[4-(2,4-dimethoxy-phenyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-4-hydroxy-6-methylpyran-2-one.

Preferred are compounds of Formula I(K):

in which A³ is defined as in the Detailed Description of the Inventionfor Formula I.; and preferably the compound of Formula I(K) which is10-(2,4-dimethoxy-phenyl)-3-methyl-7,8-dihydro-10H-2,5-dioxa-9-thia-6a-aza-cyclohepta[a]naphthalene-1,6-dione.

Preferred are compounds selected from the group consisting of:

-   -   4-hydroxy-3-[7-(2-methoxy-4-methylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one;    -   3-[7-(2-chloro-5-trifluoromethyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(4-dimethylamino-2-methoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   7-(2,4-dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepine-3-carboxylic        acid; and    -   2-({1-[7-(2,4-dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepin-3-yl]-methanoyl        }-amino)-propionic acid tert-butyl ester.

Preferred are compounds of Formula I in which A¹ is a group selectedfrom Formulae (b), (c), (d), (e) and (f):

in which R⁷ is hydrogen or methyl, R¹¹ is hydrogen or (C₁₋₆)alkyl andthe free valance is attached to A², or

A² and A¹ together with R¹ and the atoms to which A¹ and R¹ are attachedform a group of Formula (g):

wherein X¹ is —S— and the free valance is attached to A³; and

A² is as defined above or is a monocyclic or fused bicyclic ringselected from heteroarylene or unsaturated, partially unsaturated orsaturated heterocycloalkylene containing a total of 5 to 11 ring atoms,wherein A² may be substituted with a group selected from —R⁸, —X²OR⁸,—X²C(O)R⁸, —X²OC(O)R⁸, —X²C(O)OR⁸, —X²SR⁸, —X²S(O)R⁸, —X²S(O)₂R⁸,—X²NR⁴R⁸, —X²NR⁴C(O)R⁸, —X²NR⁴C(O)OR⁸, —X²C(O)NR⁴R⁸, —X²NR⁴C(O)NR⁴R⁸,—X²NR⁴C(NR⁴)NR⁴R⁸, —X²NR⁴S(O)₂R⁸ and —X²S(O)₂NR⁴R⁸, wherein X² is a bondor (C₁₋₆)alkylene, R⁸ is —X²R⁹ wherein X² is as defined above and R⁹ isaryl containing a total of 6 to 10 ring atoms, heteroaryl containing atotal of 5 to 10 ring atoms or unsaturated, partially unsaturated orsaturated carbocycloalkyl or heterocycloalkyl each containing a total of3 to 10 ring atoms, and R⁴ at each occurrence independently is hydrogen,(C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl, wherein each ring within A²and R⁸ contains from 3 to 8 ring atoms and may be substituted with 1 to3 groups independently selected from (C₁₋₆)alkyl, cyano, halo, nitro,halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶, —X²C(O)OR⁴,—X²SR⁴, —X²S(O)R⁶, —X²S (O)₂R⁶, —X²NR⁴R⁴, —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴,—X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴, —X²NR⁴C(NR⁴)NR⁴R⁴, —X²C(O)NR⁴X²C(O)OR⁴,—X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴, wherein X² and R⁴ are as defined aboveand R⁶ is (C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl, and wherein anysaid heteroalkylene, carbocycloalkyl and heterocycloalkyl rings withinA² and R⁸ may be substituted further with 1 to 2 groups independentlyselected from (C₁₋₆)alkylidene, oxo, imino and thioxo, with the provisothat only one of A² and R⁸ is a fused polycyclic ring system.

Preferred are compounds of Formula I or II in which A² is a groupselected from Formulae (h), (i), (j), (k), (l) and (m):

in which n is 1 or 2 and R¹ is acetyl or trifluoroacetyl or A² and A¹together with R¹ and the atoms to which A¹and R¹ are attached form agroup of Formula (g):

wherein X¹ is —S— and the free valance is attached to A³

Preferred are compounds of Formula I in which A¹ is selected fromFormulae (b) and (d), wherein R⁷ is hydrogen, and A² is selected fromFormulae (h) and (i).

Particularly preferred compounds of the invention include:

-   -   4-hydroxy-3-[7-(2-methoxy-4-methylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one;    -   4-hydroxy-3-[7-(4-methanesulfonyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one;    -   3-[2-(2,4-diethoxy-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one;    -   2-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-3-hydroxy-cyclohex-2-enone;    -   3-hydroxy-2-[7-(2,3,4-trimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-cyclohex-2-enone;        and    -   3-hydroxy-2-[2-(2,3,4-trimethoxy-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-cyclohex-2-enone.        Definitions

Unless otherwise stated, the following terms used in the specificationand claims are defined for the purposes of this Application and have thefollowing meanings.

“Alkyl” represented by itself means a straight or branched, saturated orunsaturated, aliphatic radical having the number of carbon atomsindicated (e.g., (C₁₋₆)alkyl includes methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl,isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl,1-propynyl, 2-propynyl, and the like). Alkyl represented along withanother radical (e.g., as in arylalkyl) means a straight or branched,saturated or unsaturated aliphatic divalent radical having the number ofatoms indicated or when no atoms are indicated means abond (e.g.,(C₆₋₁₀)aryl(C₀₋₃)alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl3-phenylpropyl, and the like).

“Alkylene”, unless indicated otherwise, means a straight or branched,saturated or unsaturated, aliphatic, divalent radical having the numberof carbon atoms indicated (e.g., (C₁₋₆)alkylene includes methylene(—CH₂—), ethylene (—CH₂CH₂—), trimethylene (—CH₂CH₂CH₂—), tetramethylene(—CH₂CH₂CH₂CH₂—), 2-butenylene (—CH₂CH═CHCH₂—), 2-methyltetramethylene(—CH₂CH(CH₃)CH₂CH₂—), pentamethylene (—CH₂CH₂CH₂CH₂CH₂—) and the like).

“Alkylidene” means a straight or branched saturated or unsaturated,aliphatic, divalent radical having the number of carbon atoms indicated(e.g. (C₁₋₆)alkylidene includes methylene (═CH₂), ethylidene (═CHCH₃),isopropylidene (═C(CH₃)₂), propylidene (═CHCH₂CH₃), allylidene(═CH—CH═CH₂), and the like).

“Amino” means the radical —NH₂. Unless indicated otherwise, thecompounds of the invention containing amino moieties include protectedderivatives thereof. Suitable protecting groups for amino moietiesinclude acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Aromatic” means a moiety wherein the constituent atoms make up anunsaturated ring system, all atoms in the ring system are sp² hybridizedand the total number of pi electrons is equal to 4n+2.

“Aryl” means an aromatic, monocyclic or fused bicyclic ring or ringassembly containing the total number of ring carbon atoms indicated,wherein each ring is comprised of 6 ring carbon atoms. Typical arylgroups containing a total of 6 to 14 ring atoms include phenyl,naphthyl, phenanthrenyl, anthracentyl, and the like. By further example,optionally substituted heteroaryl in defining A³ includes2,4-dimethoxyphenyl, 2-trifluoromethylsulfanylphenyl,3-trifluoromethylsulfanylphenyl, 4-trifluoromethylsulfanylphenyl,3-(3-trifluoromethylphenyloxy)phenyl, 3-(3,4-dichlorophenoxy)phenyl,3-(3,5-dichlorophenoxy)phenyl, 2-chloro-5-trifluoromethylphenyl,2,4-difluorophenyl, 4-dimethylaminophenyl, 4-trifluoromethoxyphenyl,2,4-di(trifluoromethyl)phenyl, 4-dimethylamino-2-methoxyphenyl,4-methylsulfonylphenyl, 2,4-diethoxyphenyl, 2,3,4-trimethoxyphenyl,2-methoxy-4-methylsulfanylphenyl, and the like.

“Carbocycloalkyl” means a monocyclic, fused bicyclic or bridgedpolycyclic ring or ring assembly containing the number of ring carbonatoms indicated. “Unsaturated, partially unsaturated or saturated” usedin connection with the term carbocycloalkyl refers to instances wherethe ring or ring assembly is unsaturated and non-aromatic (e.g.,cyclooctatetraenyl and the like), partially saturated (e.g., azulenyl,fluorenyl, indenyl,1,2,3,4-tetrahydronaphthyl, and the like) orsaturated (e.g, cyclohexyl and the like), respectively.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“Halo” means fluoro, chloro, bromo or iodo.

“Halo-substituted alkyl”, as an isolated group or part of a largergroup, means “alkyl” substituted by one or more “halo” atoms, as suchterms are defined in this Application. Halo-substituted alkyl includeshaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g.halo-substituted (C₁₋₃)alkyl includes chloromethyl, dichloromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl,2,2,2-trifluoro-1,1-dichloroethyl, and the like).

“Heteroatom moiety” includes —N═, —NR—, —O—, —S— or —S(O)₂—, wherein Ris hydrogen, (C₁₋₆)alkyl or a protecting group.

“Heteroaryl” means an aromatic, monocyclic or fused bicyclic ring orring assembly containing the total number of ring atoms indicated,wherein each ring is comprised of 5 or 6 ring atoms and one or more ofthe ring atoms is a heteroatom moiety selected from —N═, —NR—, —O— or—S—, wherein R is hydrogen, (C₁₋₆)alkyl, a protecting group orrepresents the free valence serving as the point of attachment. Forexample, aryl containing a total of 5 to 14 ring atoms includes, but isnot limited to acridine, benzo[b]thienyl, benzimidazolyl,benzoisoxazolyl, carbazolyl, β-carbolinyl, cinnolinyl, furazanyl, furyl,imidazolyl, indolizinyl, 3H-indolyl, isobenzofuranyl, isoindolyl,isothiazolyl, isoquinolyl, isoxazolyl, naphtho[2,3]thienyl,naphthyridinyl, 2-oxobenzimidaxolyl, perimidinyl, phenanthridinyl,phenazinyl, pteridinyl, purinyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, 2H-pyrrolyl, pyrroyl, quinolyl, quinoxalinyl,thienyl, and the like. By further example, optionally substitutedheteroaryl in defining A³ includes 3-phenyl-1H-pyrazol-4-yl,5-ethylthien-2-yl, 1-benzyl-1H-indol-3-yl,5-(3-trifluoromethylphenyl)fur-2-yl, 5-(2-chlorophenyl)fur-2-yl,5-(3-chlorophenyl)fur-2-yl, 5-(4-chlorophenyl)fur-2-yl,5-(2-chloro-5-trifluoromethylphenyl)fur-2-yl, 4-bromothien-2-yl,5-bromothien-2-yl, 1-phenylsulfonyl-1H-pyrrol-2-yl, 3-methylfur-2-yl,5-methylfur-2-yl, 1-methyl-1H-indol-3-yl,5-chloro-1-methyl-3-trifluoromethyl-1H-pyrrol-5-yl,4[2,2′]bithienyl-5-yl, 1-(3,5-dichloro)pyrrol-2-yl,1-(4-chloro)pyrrol-2-yl, 5-chloro-1H-indol-3-yl,6-(4-methylphenylsulfanyl)imidazo[2,1-b]thiazol-5-yl,4,5-dibromothien-2-yl, 5-methylsulfanylthien-2-yl,5-chloro-1-methyl-3-phenyl-1H-pyrrol-4-yl, and the like.

“Heteroarylene” means a divalent, aromatic, monocyclic or fused bicyclicring or ring assembly containing the total number of ring atomsindicated, wherein each ring is comprised of 5 or 6 ring atoms and twoor more of the ring atoms are a heteroatom moiety selected from —N═,—NR—, —O— or —S—, wherein R is hydrogen, (C₁₋₆)alkyl or a protectinggroup. For example, aryl containing a total of 5 to 14 ring atomsincludes, but is not limited to pyrimidin-2,4-ylene,pyrrolo[1,2-α]pyrimidin-2,4-ylene, and the like.

“Heterocycloalkylene” means a divalent, monocyclic, fused bicyclic orbridged polycyclic ring or ring assembly containing the number of ringatoms indicated, wherein two or more of the ring atoms are a heteroatommoiety selected from —N═, —NR—, —O— or —S—, wherein R is hydrogen,(C₁₋₆)alkyl or a protecting group. “Unsaturated, partially unsaturatedor saturated” used in connection with the term heterocycloalkylenerefers to instances where the ring or ring assembly is unsaturated andnon-aromatic (e.g., 1,4-thiazepin-5,7-ylene and the like), partiallysaturated (e.g., 2,3-dihydro-1,4-thiazepin-5,7-ylene,2,3-dihydrobenzo[b][1,4]thiazepin-5,7-ylene,2,3-dihydrobenzo[b][1,4]diazepin-5,7-ylene, and the like) or saturated(e.g, 1,4-thiazepan-5,7-ylene and the like), respectively. For example,optionally substituted heterocycloalkylene used in defining A² includes2,3,6,7-tetrahydro[1,4]thiazepin-5,7-ylene,2,3-dihydrobenzo[b][1,4]thiazepin-5,7-ylene,4-acetyl[1,4]thiazepan-5,7-ylene,4-trifluoroacetyl[1,4]thiazepan-5,7-ylene,2,3-dihydrobenzo[b][1,4]diazepin-5,7-ylene,2,3-dihydro-1,4-thiazepin-5,7-ylene,1-oxo-2,3,6,7-tetrahydro[1,4]thiazepin-5,7-ylene,1,1-dioxo-2,3,6,7-tetrahydro[1,4]thiazepin-5,7-ylene,3-(1-tert-butoxycarbonylethylcarbamoyl)-2,3,6,7-tetrahydro[1,4]thiazepin-5,7-ylene,and the like.

“Heterocycloalkyl” means a monocyclic, fused bicyclic or bridgedpolycyclic ring or ring assembly containing the number of ring atomsindicated. wherein one or more of the ring atoms is a heteroatom moietyselected from —N═, —NR—, —O— or —S—, wherein R is hydrogen, (C₁₋₆)alkylor a protecting group. “Unsaturated, partially unsaturated or saturated”used in connection with the term heterocycloalkyl refers to instanceswhere the ring or ring assembly is unsaturated and non-aromatic (e.g.,oxepinyl, thiepinyl, and the like), partially saturated (e.g.,2H-pyranyl, 3,6-dihydro-2H-pyran, 1,2-dihydroquinolyl, and the like) orsaturated (e.g, tetrahydropyranyl, and the like), respectively. Byfurther example, optionally substituted heterocycloalkyl used indefining A¹ includes 4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl,4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl,4-hydroxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl,2-hydroxy-6-oxo-cyclohex-1-enyl,4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl,7-amino-1-oxo-1H-isochromen-8-yl,2,3-dioxo-3,4-dihydro-2H-quinoxalin-1-yl, 2-oxo-2,3-dihydro-indol-1-yl,4-oxo-4H-pyrido[1,2-α]pyrimidin-3-yl, and the like.

“Imino” means the moiety ═NR, wherein R is hydrogen or (C₁₋₆)alkyl.

“Isomers” mean compounds of Formula I having identical molecularformulae but differ in the nature or sequence of bonding of their atomsor in the arrangement of their atoms in space. Isomers that differ inthe arrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers”. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”. A compound with one chiral center has two enantiomeric forms ofopposite chirality is termed a “racemic mixture”. A compound that hasmore than one chiral center has 2^(n−1) enantiomeric pairs, where n isthe number of chiral centers. Compounds with more than one chiral centermay exist as ether an individual diastereomers or as a mixture ofdiastereomers, termed a “diastereomeric mixture”. When one chiral centeris present a stereoisomer may be characterized by the absoluteconfiguration of that chiral center. Absolute configuration refers tothe arrangement in space of the substituents attached to the chiralcenter. Enantiomers are characterized by the absolute configuration oftheir chiral centers and described by the R- and S-sequencing rules ofCahn, Ingold and Prelog. Conventions for stereochemical nomenclature,methods for the determination of stereochemistry and the separation ofstereoisomers are well known in the art (e.g., see “Advanced OrganicChemistry”, 4th edition, March, Jerry, John Wiley & Sons, New York,1992). It is understood that the names and illustration used in thisApplication to describe compounds of Formula I are meant to beencompassed all possible stereoisomers.

“Nitro” means the radical —NO₂.

“Oxo” means the moiety ═O.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not.

“N-Oxide derivatives” means derivatives of compounds of Formula I inwhich nitrogens are in an oxidized state (i.e., O—N) and which possessthe desired pharmacological activity.

“Pathology” of a disease means the essential nature, causes anddevelopment of the disease as well as the structural and functionalchanges that result from the disease processes.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of FormulaI which are pharmaceutically acceptable, as defined above, and whichpossess the desired pharmacological activity. Such salts include acidaddition salts formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or with organic acids such as acetic acid, propionic acid,hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoicacid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

“Prodrug” means a compound which is convertible in vivo by metabolicmeans (e.g. by hydrolysis) to a compound of the invention. For examplean ester of a compound of the invention containing a hydroxy group maybe convertible by hydrolysis in vivo to the parent molecule.Alternatively an ester of a compound of the invention containing acarboxy group may be convertible by hydrolysis in vivo to the parentmolecule. Suitable esters of compounds of the invention containing ahydroxy group, are for example acetates, citrates, lactates, tartrates,malonates, oxalates, salicylates, propionates, succinates, fumarates,maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,di-p-toluoyltartrates, methanesulphonates, ethanesulphonates,benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates andquinates. Suitable esters of compounds of the invention containing acarboxy group, are for example those described by F. J. Leinweber, DrugMetab. Res., 1987, 18, page 379. An especially useful class of esters ofcompounds of the invention containing a hydroxy group, may be formedfrom acid moieties selected from those described by Bundgaard et al., J.Med. Chem., 1989, 32, page 2503-2507, and include substituted(aminomethyl)-benzoates, for example, dialkylamino-methylbenzoates inwhich the two alkyl groups may be joined together and/or interrupted byan oxygen atom or by an optionally substituted nitrogen atom, e.g. analkylated nitrogen atom, more especially (morpholino-methyl)benzoates,e.g. 3- or 4-(morpholinomethyl)-benzoates, and(4-alkylpiperazin-1-yl)benzoates, e.g. 3- or4-(4-alkylpiperazin-1-yl)benzoates.

“Protected derivatives” means derivatives of compounds of the inventionin which a reactive site or sites are blocked with protecting groups.Protected derivatives of compounds of the invention are useful in thepreparation of compounds of the invention or in themselves may be activeas activators of the caspase cascade and inducers of apoptosis. Acomprehensive list of suitable protecting groups can be found in T. W.Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley& Sons, Inc. 1999.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Thioxo” means the moiety=S.

“Treatment” or “treating” means any administration of acompound of thepresent invention and includes:

-   -   (1) preventing the disease from occurring in an animal which may        be predisposed to the disease but does not yet experience or        display the pathology or symptomatology of the disease,    -   (2) inhibiting the disease in an animal that is experiencing or        displaying the pathology or symptomatology of the diseased        (i.e., arresting further development of the pathology and/or        symptomatology), or    -   (3) ameliorating the disease in an animal that is experiencing        or displaying the pathology or symptomatology of the diseased        (i.e., reversing the pathology and/or symptomatology).        Nomenclature

The compounds of Formulae I and II and the intermediates and startingmaterials used in their preparation are named in accordance with IUPACrules of nomenclature in which the characteristic groups have decreasingpriority for citation as the principle group, e.g., acids, esters,amides, etc, as determined by AutoNom 4.0 (Beilstein InformationSystems, Inc.). For example, a compound of Formula II wherein A¹ is4-hydroxy-6-methyl-2-oxopyran-3-yl, A² is2,3,6,7-tetrahydro[1,4]thiazepin-5,7-ylene and A³ is3-(3,5-dichloro-phenoxy)-phenyl is named3-{7-[3-(3,5-dichloro-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one.Alternatively, the compound may be referred to as5-(4-hydroxy-6-methyl-2H-pyran-2-one-3-yl)-7-[3-(3,5-dichloro-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepine.

Utility and Pharmacology

Another important aspect of the present invention is the discovery thatsubstituted 1,4-thiazepines and analogs thereof are potent and highlyefficacious activators of caspases and inducers of apoptosis in drugresistant cancer cells, such as breast and prostate cancer cells, whichenables these compounds to kill these drug resistant cancer cells. Incomparison, most standard anti-cancer drugs are not effective in killingdrug resistant cancer cells under the same conditions. Therefore,substituted 1,4-thiazepines and analogs thereof are useful for thetreatment of drug resistant cancer in animals.

The present invention includes a therapeutic method useful to modulatein vivo apoptosis or in vivo neoplastic disease, comprisingadministering to a subject in need of such treatment an effective amountof a substituted 1,4-thiazepines or analog thereof, or apharmaceutically acceptable salt or prodrug thereof, which functions asa caspase cascade activator and inducer of apoptosis.

The present invention also includes a therapeutic method comprisingadministering to an animal an effective amount of a substituted1,4-thiazepines or analog thereof, or a pharmaceutically acceptable saltor prodrug thereof, wherein said therapeutic method is useful to treatcancer, which is a group of diseases characterized by the uncontrolledgrowth and spread of abnormal cells. Such diseases include, but are notlimited to, Hodgkin's disease, non-Hodgkin's lymphomas, acute andchronic lymphocytic leukemias, multiple myeloma, neuroblastoma, breastcarcinomas, ovarian carcinomas, lung carcinomas, Wilms' tumor, cervicalcarcinomas, testicular carcinomas, soft tissue sarcomas, chroniclymphocytic leukemia, primary macroglobulinemia, bladder carcinomas,chronic granulocytic leukemia, primary brain carcinomas, malignantmelanoma, small-cell lung carcinomas, stomach carcinomas, coloncarcinomas, malignant pancreatic insulinoma, malignant carcinoidcarcinomas, malignant melanomas, choriocarcinomas, mycosis fungoides,head and neck carcinomas, osteogenic sarcoma, pancreatic carcinomas,acute granulocytic leukemia, hairy cell leukemia, neuroblastoma,rhabdomyo sarcoma, Kaposi's sarcoma, genitourinary carcinomas, thyroidcarcinomas, esophageal carcinomas, malignant hypercalcemia, cervicalhyperplasia, renal cell carcinomas, endometrial carcinomas, polycythemiavera, essential thrombocytosis, adrenal cortex carcinomas, skin cancer,and prostatic carcinomas.

In practicing the therapeutic methods, effective amounts of compositionscontaining therapeutically effective concentrations of the compoundsformulated for oral, intravenous, local and topical application, for thetreatment of neoplastic diseases and other diseases in which caspasecascade mediated physiological responses are implicated, areadministered to an individual exhibiting the symptoms of one or more ofthese disorders. The amounts are effective to ameliorate or eliminateone or more symptoms of the disorders. An effective amount of a compoundfor treating a particular disease is an amount that is sufficient toameliorate, or in some manner reduce the symptoms associated with thedisease. Such amount may be administered as a single dosage or may beadministered according to a regimen, whereby it is effective. The amountmay cure the disease but, typically, is administered in order toameliorate the disease. Typically, repeated administration is requiredto achieve the desired amelioration of symptoms.

In another embodiment, a pharmaceutical composition comprising asubstituted 1,4-thiazepines or analog thereof, or a pharmaceuticallyacceptable salt thereof, which functions as a caspase cascade activatorand inducer of apoptosis in combination with a pharmaceuticallyacceptable vehicle is provided.

Another embodiment of the present invention is directed to a compositioneffective to inhibit neoplasia comprising a substituted 1,4-thiazepinesor analog thereof, or a pharmaceutically acceptable salt or prodrugthereof, which functions as a caspase cascade activator and inducer ofapoptosis, in combination with at least one known cancerchemotherapeutic agent, or a pharmaceutically acceptable salt of saidagent. Examples of known anticancer agents which can be used forcombination therapy include, but not are limit to alkylating agents suchas busulfan, cis-platin, mitomycin C, and carboplatin; antimitoticagents such as colchicine, vinblastine, paclitaxel, and docetaxel; topoI inhibitors such as camptothecin and topotecan; topo II inhibitors suchas doxorubicin and etoposide; RNA/DNA antimetabolites such as5-azacytidine, 5-fluorouracil and methotrexate; DNA antimetabolites suchas 5-fluoro-2′-deoxy-uridine, ara-C, hydroxyurea and thioguanine; andantibodies such as Herceptin® and Rituxan®. Other known anti-canceragents which can be used for combination therapy include melphalan,chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone,epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium,fludarabine, octreotide, retinoic acid, tamoxifen and alanosine.

In practicing the methods of the present invention, the substituted1,4-thiazepines or analog thereof may be administered together with atleast one known chemotherapeutic agent as part of a unitarypharmaceutical composition. Alternatively, the compound of the inventionmay be administered apart from at least one known cancerchemotherapeutic agent. In one embodiment, the compound of the inventionand at least one known cancer chemotherapeutic agent are administeredsubstantially simultaneously, i.e. the compounds are administered at thesame time or one after the other, so long as the compounds reachtherapeutic levels in the blood at the same time. In another embodiment,the compound of the invention and at least one known cancerchemotherapeutic agent are administered according to their individualdose schedule, so long as the compounds reach therapeutic levels in theblood.

Another embodiment of the present invention is directed to a compositioneffective to inhibit neoplasia comprising a bioconjugates of thesubstituted 1,4-thiazepines or analogs thereof, which functions as acaspase cascade activator and inducer of apoptosis, in bioconjugationwith at least one known therapeutically useful antibody, such asHerceptin® or Rituxan®, growth factor such as DGF or NGF, cytokines suchas IL-2 or IL-4, or any other molecule that binds to a cell surfacereceptor. These conjugates can be made using functional groups of thesubstituted 1,4-thiazepines or analogs thereof. For example. when one ofthe R groups is a carboxylic acid, it can be used to modify the aminogroup on the proteins, to produced a drug-protein conjugate. Forexample, the N-hydroxysuccinamide ester of the carboxy-containingcompound may be prepared which may be condensed with the protein. SeeAnal. Biochem 87:218 (1994) and Polycyclic Aromat. Compd 3:781 (1993).The antibodies and other molecules will deliver the substituted1,4-thiazepine or analog thereof to its targets and make them moreeffective anticancer agents. The bioconjugates also may enhance theanticancer effect of therapeutically useful antibodies, such asHerceptin® or Rituxan®.

Similarly, another embodiment of the present invention is directed to acomposition effective to inhibit neoplasia comprising a substituted1,4-thiazepine or analog thereof, or a pharmaceutically acceptable saltor prodrug thereof, which functions as a caspase cascade activator andinducer of apoptosis, in combination with radiation therapy. In thisembodiment, the substituted 1,4-thiazepine or analog thereof may beadministered at the same time as the radiation therapy is administeredor at a different time.

Yet another embodiment of the present invention is directed to acomposition effective for post-surgical treatment of cancer, comprisinga substituted 1,4-thiazepine or analog thereof, or a pharmaceuticallyacceptable salt or prodrug thereof, which functions as a caspase cascadeactivator and inducer of apoptosis. The invention also relates to amethod of treating cancer by surgically removing the cancer and thentreating the animal with one of the pharmaceutical compositionsdescribed herein.

A wide range of immune mechanisms operate rapidly following exposure toan infectious agent. Depending on the type of infection, rapid clonalexpansion of the T and B lymphocytes occurs to combat the infection. Theelimination of the effector cells following an infection is one of themajor mechanisms maintaining immune homeostasis. This deletion ofreactive cell has been shown to be regulated by a phenomenon known asapoptosis. Autoimmune diseases have been lately identified as aconsequence of deregulated cell death. In certain autoimmune diseases,the immune system directs its powerful cytotoxic effector mechanismsagainst specialized cells such as oligodendrocytes in multiplesclerosis, the beta cells of the pancreas in diabetes mellitus, andthyrocytes in Hashimoto's thyroiditis (Ohsako. S. & Elkon, K. B., CellDeath Differ. 6:13-21 (1999)). Mutations of the gene encoding thelymphocyte apoptosis receptor Fas/APO-1/CD95 are reported to beassociated with defective lymphocyte apoptosis and autoimmunelymphoproliferative syndrome (ALPS), which is characterized by chronic,histologically benign splenomegaly and generalized lymphadenopathy,hypergammaglobulinemia, and autoantibody formation (Infante, A. J., etal., J Pediatr. 133:629-633 (1998) and Vaishnaw, A. K., et al., J Clin.Invest. 103:355-3)63 (1999)). Overexpression of Bcl-2, which is a memberof the bcl-2 gene family of programmed cell death regulators withanti-apoptotic activity in developing B cells of transgenic mice, in thepresence of T cell dependent co-stimulatory signals, results in thegeneration of a modified B cell repertoire and in the production ofpathogenic autoantibodies (Lopez-Hoyos, M., et al., Int. J MoL Med.1:475-483 (1998)). Accordingly, many types of autoimmune disease may becaused by defects of the apoptotic process, and one treatment strategywould be to turn on apoptosis in the lymphocytes that are causingautoimmune disease (O'Reilly, L. A. & Strasser, A., Inflamm. Res.48:5-21 (1999)).

Fas-Fas ligand (FasL) interaction is known to be required for themaintenance of immune homeostasis. Experimental autoimmune thyroiditis(EAT), characterized by autoreactive T and B cell responses and a markedlymphocytic infiltration of the thyroid, is a good model to study thetherapeutic effects of FasL. Batteux, F., et al., (J Immunol.162:603-608 (1999)) reported that by direct injection of DNA expressionvectors encoding FasL into the inflamed thyroid, the development oflymphocytic infiltration of the thyroid was inhibited and induction ofinfiltrating T cells death was observed. These results show that FasLexpression on thyrocytes may have a curative effect on ongoing EAT byinducing death of pathogenic autoreactive infiltrating T lymphocytes.

Bisindolylmaleimide VIII is known to potentiate Fas-mediated apoptosisin human astrocytoma 1321NI cells and in Molt-4T cells, and both ofwhich were resistant to apoptosis induced by anti-Fas antibody in theabsence of bisindolylmaleimide VIII. Potentiation of Fas-mediatedapoptosis by bisindolylmaleimide VIII was reported to be selective foractivated, rather than non-activated, T cells, and was Fas-dependent.Zhou T., el al., (Nat. Med 5:42-49 (1999)) reported that administrationof bisindolylmaleimide VIII to rats during autoantigen stimulationprevented the development of symptoms of T cell-mediated autoimmunediseases in two models, the Lewis rat model of experimental allergicencephalitis and the Lewis adjuvant arthritis model. Therefore theapplication of a Fas-dependent apoptosis enhancer such asbisindolylmaleimide VIII may be therapeutically useful for the moreeffective elimination of detrimental cells and inhibition of Tcell-mediated autoimmune diseases. Therefore an effective amount of asubstituted 1,4-thiazepines or analog thereof, or a pharmaceuticallyacceptable salt or prodrug thereof, which functions as a caspase cascadeactivator and inducer of apoptosis, should be an effective treatment forautoimmune disease

Psoriasis is a chronic skin disease that is characterized by scaly redpatches. Psoralen plus ultraviolet A (PUVA) is a widely used andeffective treatment for psoriasis vulgaris and Coven, et al.,Photodermatol. Photoimmunol. Photomed 15:22-27 (1999), reported thatlymphocytes treated with psoralen 8-MOP or TMP plus UVA displayed DNAdegradation patterns typical of apoptotic cell death. Ozawa, et al., JExp. Med 189:711-718 (1999) reported that induction of T cell apoptosiscould be the main mechanism by which 312-nm UVB resolves psoriasis skinlesions. Low doses of methotrexate may be used to treat psoriasis torestore a clinically normal skin. Heenen, et al., Arch. Dermatol. Res.290:240-245 (1998), reported that low doses of methotrexate may induceapoptosis and this mode of action could explain the reduction inepidermal hyperplasia during treatment of psoriasis with methotrexate.Therefore an effective amount of a substituted 1,4-thiazepine or analogthereof, or a pharmaceutically acceptable salt or prodrug thereof, whichfunctions as a caspase cascade activator and inducer of apoptosis,should be an effective treatment for psoriasis.

Synovial cell hyperplasia is a characteristic of patients withrheumatoid arthritis (RA). Excessive proliferation of RA synovial cellsas well as defects in synovial cell death might be responsible for thesynovial cell hyperplasia. Wakisaka, et al., Clin. Exp. Immunol.114:119-128 (1998), found that although RA synovial cells could die viaapoptosis through Fas/FasL pathway, apoptosis of synovial cells wasinhibited by proinflammatory cytokines present within the synovium, andsuggested that inhibition of apoptosis by the proinflammatory cytokinesmay contribute to the outgrowth of synovial cells, and lead to pannusformation and the destruction of joints in patients with RA. Thereforean effective amount of a substituted 1,4-thiazepine or analog thereof,or a pharmaceutically acceptable salt or prodrug thereof, whichfunctions as a caspase cascade activator and inducer of apoptosis,should be an effective treatment for rheumatoid arthritis.

An accumulation of convincing evidence suggests that apoptosis plays amajor role in promoting resolution of the acute inflammatory response.Neutrophils are constitutively programmed to undergo apoptosis, thuslimiting their pro-inflammatory potential and leading to rapid,specific, and non-phlogistic recognition by macrophages andsemi-professional phagocytes (Savill, J., J Leukoc. Biol. 61:375-380(1997)). Boirivant, et al., Gastroenterology 116:557-565 (1999),reported that lamina propria T cells isolated from areas of inflammationin Crohn's disease, ulcerative colitis, and other inflammatory statesmanifest decreased CD2 pathway-induced apoptosis, and that studies ofcells from inflamed Crohn's disease tissue indicate that this defect isaccompanied by elevated Bel-2 levels. Therefore an effective amount of asubstituted 1,4-thiazepines or analog thereof, or a pharmaceuticallyacceptable salt or prodrug thereof, which functions as a caspase cascadeactivator and inducer of apoptosis, should be an effective treatment forinflammation and inflammatory bowel disease.

Compositions within the scope of this invention include all compositionswherein the caspase cascade activators are contained in an amount thatis effective to achieve its intended purpose. While individual needsvary, determination of optimal ranges of effective amounts of eachcomponent is within the skill of the art. Typically, the activecompounds may be administered to mammals, e.g., humans, orally at a doseof 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceuticallyacceptable salt thereof, per day of the body weight of the mammal beingtreated for apoptosis mediated disorders. Preferably, about 0.01 toabout 10 mg/kg is orally administered to treat or prevent suchdisorders. For intramuscular injection, the dose is generally aboutone-half of the oral dose. For example, a suitable intramuscular dosewould be about 0.0025 to about 25 mg/kg, and most preferably, from about0.01 to about 5 mg/kg. If a known cancer chemotherapeutic agent is alsoadministered, it is administered in an amount with is effective toachieve its intended purpose. The amounts of such known cancerchemotherapeutic agents effective for cancer are well known to those ofskill in the art.

The unit oral dose may comprise from about 0.01 to about 50 mg,preferably about 0.1 to about 10 mg of the caspase cascade activator.The unit dose may be administered one or more times daily as one or moretablets each containing from about 0.1 to about 10, conveniently about0.25 to 50 mg of the compound or its solvates. In a topical formulation,the caspase cascade activator may be present at a concentration of about0.01 to 100 mg per gram of carrier.

In addition to administering the caspase cascade activator as a rawchemical, the caspase cascade activator may be administered as part of apharmaceutical preparation containing suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries whichfacilitate processing of the compounds into preparations which can beused pharmaceutically. Preferably, the preparations, particularly thosepreparations which can be administered orally and which can be used forthe preferred type of administration, such as tablets, dragees, andcapsules, and also preparations which can be administered rectally, suchas suppositories, as well as suitable solutions for administration byinjection or orally, contain from about 0.01 to 99 percent, preferablyfrom about 0.25 to 75 percent of active compound(s), together with theexcipient.

Also included within the scope of the present invention are the nontoxicpharmaceutically acceptable salts of the compounds of the presentinvention. Acid addition salts are formed by mixing a solution of theparticular apoptosis inducer with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, and the like. Basic saltsare formed by mixing a solution of the particular apoptosis inducers ofthe present invention with a solution of a pharmaceutically acceptablenon-toxic base such as sodium hydroxide, potassium hydroxide, cholinehydroxide, sodium carbonate, Tris, N-methyl-glucamine and the like.

The pharmaceutical compositions of the invention may be administered toany animal which may experience the beneficial effects of the compoundsof the invention. Foremost among such animals are mammals, e.g., humansand veterinary animals, although the invention is not intended to be solimited.

The pharmaceutical compositions of the present invention may beadministered by any means that achieve their intended purpose. Forexample, administration may be by parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, buccal, intrathecal,intracranial, intranasal or topical routes. Alternatively, orconcurrently, administration may be by the oral route. The dosageadministered will be dependent upon the age, health, and weight of therecipient, kind of concurrent treatment, if any, frequency of treatment,and the nature of the effect desired.

The pharmaceutical preparations of the present invention aremanufactured in a manner which is itself known, for example, by means ofconventional mixing, granulating, dragee-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usecan be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as saccharides, forexample lactose or sucrose, mannitol or sorbitol, cellulose preparationsand/or calcium phosphates, for example tricalcium phosphate or calciumhydrogen phosphate, as well as binders such as starch paste, using, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose,sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,disintegrating agents may be added such as the above-mentioned starchesand also carboxymethyl-starch, crosslinked polyvinyl pyrrolidone, agar,or alginic acid or a salt thereof, such as sodium alginate. Auxiliariesare, above all, flow-regulating agents and lubricants, for example,silica, talc, stearic acid or salts thereof, such as magnesium stearateor calcium stearate, and/or polyethylene glycol. Dragee cores areprovided with suitable coatings which, if desired, are resistant togastric juices. For this purpose, concentrated saccharide solutions maybe used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquersolutions and suitable organic solvents or solvent mixtures. In order toproduce coatings resistant to gastricjuices, solutions of suitablecellulose preparations such as acetylcellulose phthalate orhydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs orpigments may be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses. Other pharmaceutical preparations which can be usedorally include push-fit capsules made of gelatin, as well as soft,sealed capsules made of gelatin and a plasticizer such as glycerol orsorbitol. The push-fit capsules can contain the active compounds in theform of granules which may be mixed with fillers such as lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In soft capsules, the activecompounds are preferably dissolved or suspended in suitable liquids,such as fatty oils, or liquid paraffin. In addition, stabilizers may beadded. Possible pharmaceutical preparations which can be used rectallyinclude, for example, suppositories, which consist of a combination ofone or more of the active compounds with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,or paraffin hydrocarbons. In addition, it is also possible to usegelatin rectal capsules which consist of a combination of the activecompounds with a base. Possible base materials include, for example,liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, for example, sesame oil, or synthetic fatty acid esters, forexample, ethyl oleate or triglycerides or polyethylene glycol-400 (thecompounds are soluble in PEG-400). Aqueous injection suspensions maycontain substances which increase the viscosity of the suspension, andinclude, for example, sodium carboxymethyl cellulose, sorbitol, and/ordextran. Optionally, the suspension may also contain stabilizers. Inaccordance with one aspect of the present invention, substituted1,4-thiazepines or analogs thereof, or a pharmaceutically acceptablesalt or prodrug thereof, are employed in topical and parenteralformulations and are used for the treatment of skin cancer.

The topical compositions of this invention are formulated preferably asoils, creams, lotions, ointments and the like by choice of appropriatecarriers. Suitable carriers include vegetable or mineral oils, whitepetrolatum (white soft paraffin), branched chain fats or oils, animalfats and high molecular weight alcohol (greater than C₁₂). The preferredcarriers are those in which the active ingredient is soluble.Emulsifiers, stabilizers, humectants and antioxidants may also beincluded as well as agents imparting color or fragrance, if desired.Additionally, transdermal penetration enhancers can be employed in thesetopical formulations. Examples of such enhancers can be found in U.S.Pat. Nos. 3,989,816 and 4,444,762.

Creams are preferably formulated from a mixture of mineral oil, selfemulsifying beeswax and water in which mixture the active ingredient,dissolved in a small amount of an oil such as almond oil, is admixed. Atypical example of such a cream is one which includes about 40 partswater, about 20 parts beeswax, about 40 parts mineral oil and about 1part almond oil.

Ointments may be formulated by mixing a solution of the activeingredient in a vegetable oil such as almond oil with warm soft paraffinand allowing the mixture to cool. A typical example of such an ointmentis one which includes about 30% almond oil and about 70% white softparaffin by weight.

Accordingly, an aspect of the present invention is a method of treatinga disorder responsive to the induction of apoptosis in an animalsuffering from said disorder, which method comprises administering tothe animal an effective amount of a compound of Formula I:

in which:

the dashed lines indicate optional unsaturation without violatingvalency rules;

R¹ is hydrogen, (C₁₋₆)alkyl or —C(O)R⁶, wherein R⁶ is as defined below,or is absent when a double bond exists between the nitrogen atom towhich R¹ is attached and an adjacent ring atom or R¹ is as definedbelow;

X¹ is —NR²—, —S—, —S(O)—, —S(O)₂— or —O—, wherein R² is hydrogen or(C₁₋₆)alkyl or is absent when a double bond exists between the nitrogenatom to which R² is attached and an adjacent ring atom;

A¹ is a monocyclic or fused polycyclic ring system selected from arylcontaining a total of 6 to 14 ring atoms, heteroaryl containing a totalof 5 to 14 ring atoms and unsaturated, partially unsaturated orsaturated carbocycloalkyl or heterocycloalkyl each containing a total of3 to 14 ring atoms, or A¹ together with R¹ and the atoms to which A¹ andR¹ are attached forms a fused polycyclic ring system selected fromheteroaryl and unsaturated, partially unsaturated or saturatedheterocycloalkyl in any case containing a total of 10 to 15 ring atoms,wherein A¹ may be substituted with a group selected from —R³, —X²OR³,—X²C(O)R³, —X²OC(O)R³, —X²C(O)OR³, —X²SR³, —X²S(O)R³, —X²S(O)₂R³,—X²NR³R⁴, —X²NR⁴C(O)R³, —X²NR⁴C(O)OR³, —X²C(O)NR³R⁴, —X²NR⁴C(O)NR³R⁴,—X²NR⁴C(NR⁴)NR³R⁴, —X²NR⁴S(O)₂R³ and —X²S(O)₂NR³R⁴, wherein X² is a bondor (C₁₋₆)alkylene, R³ is —X²R⁵ wherein X² is as defined above and R⁵ isaryl containing a total of 6 to 10 ring atoms, heteroaryl containing atotal of 5 to 10 ring atoms or unsaturated, partially unsaturated orsaturated carbocycloalkyl or heterocycloalkyl each containing a total of3 to 10 ring atoms, and R⁴ at each occurrence independently is hydrogen,(C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl, wherein each ring within A¹and R⁵ contains from 3 to 8 ring atoms and may be substituted with 1 to3 groups independently selected from (C₁₋₆)alkyl, cyano, halo, nitro,halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶, —X²C(O)OR⁴,—X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴, —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴,—X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴, —X²NR⁴C(NR⁴)NR⁴R⁴, —X²NR⁴S(O)₂R⁶ and—X²S(O)₂NR⁴R⁴, wherein X² and R⁴ are as defined above and R⁶ is(C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl, and wherein any saidcarbocycloalkyl and heterocycloalkyl rings within A¹ and R⁵ may besubstituted further with 1 to 2 groups independently selected from(C₁₋₆)alkylidene, oxo, imino and thioxo, with the provisos that only oneof A¹ and R⁵ is a fused polycyclic ring system;

-   -   A² is a monocyclic or fused bicyclic ring selected from        heteroarylene or unsaturated, partially unsaturated or saturated        heterocycloalkylene containing a total of 5 to 11 ring atoms,        wherein A² may be substituted with a group selected from —R⁸,        —X²OR⁸, —X²C(O)R⁸, —X²OC(O)R⁸, —X²C(O)OR⁸, —X²SR⁸, —X²S(O)R⁸,        —X²S(O)₂R⁸, —X²NR⁴R⁸, —X²NR⁴C(O)R⁸, —X²NR⁴C(O)OR⁸, —X²C(O)NR⁴R⁸,        —X²NR⁴C(O)NR⁴R⁸, —X²NR⁴C(NR⁴)NR⁴R⁸, —X²NR⁴S(O)₂R⁸ and        —X²S(O)₂NR⁴R⁸, wherein X² is abond or (C₁₋₆)alkylene, R⁸ is        —X²R⁹ wherein X² is as defined above and R⁹ is aryl containing a        total of 6 to 10 ring atoms, heteroaryl containing a total of 5        to 10 ring atoms or unsaturated, partially unsaturated or        saturated carbocycloalkyl or heterocycloalkyl each containing a        total of 3 to 10 ring atoms, and R⁴ at each occurrence        independently is hydrogen, (C1-6)alkyl or halo-substituted        (C₁₋₆)alkyl, wherein each ring within A² and R⁸ contains from 3        to 8 ring atoms and may be substituted with 1 to 3 groups        independently selected from (C₁₋₆)alkyl, cyano, halo, nitro,        halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶,        —X²C(O)OR⁴, —X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴,        —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴, —X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴,        —X²NR⁴C(NR⁴)NR⁴R⁴, —X²C(O)NR⁴X²C(O)OR⁴, —X²NR⁴S(O)₂R⁶ and        —X²S(O)₂NR⁴R⁴, wherein x² and R⁴ are as defined above and R⁶ is        (C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl, and wherein any        said heterocycloalkylene, carbocycloalkyl and heterocycloalkyl        rings within A² and R⁸ may be substituted further with 1 to 2        groups independently selected from (C₁₋₆)alkylidene, oxo, imino        and thioxo, with the proviso that only one of A² and R⁸ is a        fused polycyclic ring system; and    -   A³ is a monocyclic or fused polycyclic ring system selected from        aryl containing a total of 6 to 14 ring atoms, heteroaryl        containing a total of 5 to 14 ring atoms and unsaturated,        partially unsaturated or saturated carbocycloalkyl or        heterocycloalkyl each containing a total of 3 to 14 ring atoms,        wherein A³ may be substituted with a group selected from —R⁹,        —X²R⁹, —X²C(O)R⁹, —X²C(O)R⁹, —X²C(O)OR⁹, —X²SR⁹, —X²S(O)R⁹,        —X²S(O)₂R⁹, —X²NR⁴R⁹, —X²NR⁴C(O)R⁹, —X²NR⁴C(O)OR⁹, —X²C(O)NR⁴R⁹,        —X²NR⁴C(O)NR⁴R⁹, —X²NR⁴C(NR⁴)NR⁴R⁹, —X²NR⁴S(O)₂R⁹ and        —X²S(O)₂NR⁴R⁹, wherein X² is a bond or (C₁₋₆)alkylene, R⁹ is        —X²R¹⁰ wherein X² is as defined above and R¹⁰ is aryl containing        a total of 6 to 10 ring atoms, heteroaryl containing a total of        5 to 10 ring atoms or unsaturated, partially unsaturated or        saturated carbocycloalkyl or heterocycloalkyl each containing a        total of 3 to 10 ring atoms, and R⁴ at each occurrence        independently is hydrogen, (C₁₋₆)alkyl or halo-substituted        (C₁₋₆)alkyl, wherein each ring within A³ and R¹⁰ contains from 3        to 8 ring atoms and may be substituted with 1 to 3 groups        independently selected from (C¹⁻⁶)alkyl, cyano, halo, nitro,        halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶,        —X²C(O)OR⁴, —X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴,        —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴, —X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴,        —X²NR⁴C(NR⁴)NR⁴R⁴, —X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴, wherein X²        and R⁴ are as defined above and R⁶ is (C₁₋₆)alkyl or        halo-substituted (C₁₋₆)alkyl, and wherein any said        carbocycloalkyl and heterocycloalkyl rings within A³ and R¹⁰ may        be substituted further with 1 to 2 groups independently selected        from (C₁₋₄)alkylidene, oxo, imino and thioxo, with the proviso        that only one of A³ and R¹⁰ is a fused polycyclic ring system;        or an N-oxide derivative, prodrug derivative, protected        derivative, individual stereoisomer or mixture of stereoisomers,        or a pharmaceutically acceptable salt thereof; with the proviso        that when said compound is of Formula II(a):        then A³ is other than:    -   (a) benzo[1,3]dioxolyl;    -   (b) phenyl which is mono-substituted by bromo, hydroxy, methyl        or isopropyl; and    -   (c) phenyl which is substituted by at least one of chloro and        methoxy and not substituted by methylsulfanyl, amino,        methylamino or dimethylamino; preferably wherein said disorder        is an autoimmune disease, in particular rheumatoid arthritis, or        inflammation or inflammatory bowel disease, in particular,        wherein said disorder is psoriasis or a skin disease.

Another aspect of the present invention is a method for treating orpreventing cancer, comprising administering to an animal in need of suchtreatment an effective amount of a compound of Formula I as definedimmediately above; particularly wherein said cancer is selected from thegroup consisting of Hodgkin's disease, non-Hodgkin's lymphoma, acute andchronic lymphocytic leukemias, multiple myeloma, neuroblastoma, breastcarcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervicalcarcinoma, testicular carcinoma, soft-tissue sarcoma, chroniclymphocytic leukemia, primary macroglobulinemia, bladder carcinoma,chronic granulocytic leukemia, primary brain carcinoma, malignantmelanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma,malignant pancreatic insulinoma, malignant carcinoid carcinoma,choriocarcinoma, mycosis fungoides, head and neck carcinoma, osteogenicsarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cellleukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma,genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma,malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma,endometrial carcinoma, polycythemia vera, essential thrombocytosis,adrenal cortex carcinoma, skin cancer and prostatic carcinoma.

Another aspect of the present invention is a method for the treatment ofdrug resistant cancer, comprising administering to an animal in need ofsuch treatment an effective amount of a compound of compound of FormulaI as defined immediately above.

Preferred means for practicing any of the above methods comprisesfurther administering to said animal at least one known cancerchemotherapeutic agent, or a pharmaceutically acceptable salt of saidagent; preferably wherein said known cancer therapeutic agent isselected from the group consisting of busulfan, cis-platin, mitomycin C,carboplatin, colchicine, vinblastine, paclitaxel, docetaxel,camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine,5-fluorouracil, methotrexate, 5-fluoro-2′-deoxy-uridine, ara-C,hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide,ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin,bleomycin, imitoxantrone, elliptinium, fludarabine, octreotide, retinoicacid, tamoxifen, Herceptin®, Rituxan® and alanosine.

Preferred means for practicing any of the above methods comprisesfurther treating said animal with radiation-therapy.

Preferred means for practicing any of the above methods comprisesadministering the compound of Formula I after surgical treatment forcancer.

Preferred means for practicing any of the above methods comprisesadministering a compound of Formula I which when said compound isselected from the group consisting of Formula II(a) and II(b):

then A³ is other than:

-   -   (a) benzo[1,3]dioxolyl;    -   (b) phenyl which is mono-substituted by bromo, nitro, hydroxy,        methyl or isopropyl; and    -   (c) phenyl which is substituted by at least one of Cl and        methoxy and not substituted by methylsulfanyl, amino,        methylamino and dimethylamino    -   A further preferred means for practicing any of the above        methods comprises administering a compound of Formula I which        when said compound is selected from the group consisting of        Formula II(a) and II(b), then A³ is other than        benzo[1,3]dioxol-5-yl, 2,3-dihydro-benzo[1,4]dioxinyl or phenyl        which is substituted by at least one of bromo, chloro, hydroxy,        nitro, methoxy and (C₁₋₃)alkyl    -   A further preferred means for practicing any of the above        methods comprises administering a compound of Formula I in which        A¹ of said compound is a group selected from Formulae (a), (b),        (c), (d) and (e):        in which R⁷ is hydrogen or methyl, R¹¹ is hydrogen or        (C₁₋₆)alkyl and the free valance is attached to A², or    -   A² and A¹ together with R¹ and the atoms to which A¹ and R¹ are        attached forms a group of Formula (g):        wherein X¹ is —S— and the free valance is attached to A³; and    -   A² of said compound is as defined above or is a group selected        from Formulae (h), (i), (j), (k), (l) and (m):        in which n is 1 or 2 and R¹ is acetyl or trifluoroacetyl.

A further preferred means for practicing any of the above methodscomprises administering a compound of Formula I in which A³ is phenyl orheteroaryl containing a total of 5 to 9 ring atoms, wherein A³ may besubstituted with a group selected from —R⁹, —X²OR⁹, —X²SR⁹ and—X²S(O)₂R⁹, wherein R⁹ is —X²R¹⁰, X² is a bond or (C₁₋₆alkylene and R¹⁰is phenyl or heteroaryl containing a total of 5 to 6 ring atoms, whereineach ring within A³ and R¹⁰ may be substituted with 1 to 3 groupsindependently selected from (C₁₋₆)alkyl, halo, halo-substituted(C₁₋₆)alkyl, —X²OR⁴, —X²SR⁴, —X²S(O)₂R⁶ and —X²NR⁴R⁴, wherein R⁴ at eachoccurrence independently is hydrogen, (C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl and R⁶ is (C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl.

A further preferred means for practicing any of the above methodscomprises administering a compound of Formula I, wherein said compoundis selected from the group consisting of:

-   -   4-hydroxy-3-[7-(2-methoxy4-methyl        sulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one;    -   2-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-3-hydroxy-cyclohex-2-enone;    -   4-hydroxy-3-[7-(4-methanesulfonyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one;    -   3-[2-(2,4-diethoxy-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5        ,6-dihydro-pyran-2-one;    -   3-[7-(4-dimethylamino-phenyl)-2,3,6,7-tetrahydro-1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one;    -   2-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-3-hydroxy-cyclohex-2-enone;    -   3-hydroxy-2-[7-(2,3,4-trimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-cyclohex-2-enone;    -   3-hydroxy-2-[2-(2,3,4-trimethoxy-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-cyclohex-2-enone;    -   4-hydroxy-6-methyl-3-[2-(2,3,4-trimethoxy-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-5,6-dihydro-pyran-2-one;    -   4-hydroxy-6-methyl-3-[7-(2,3,4-trimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-5,6-dihydro-pyran-2-one;        and    -   3-[7-(2,4-dimethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]4-hydroxy-6-methyl-pyran-2-one;

A further preferred means for practicing any of the above methodscomprises administering a compound of Formula I, wherein said compoundis selected from the group consisting of:

-   -   3-[4-acetyl-7-(2,4-dimethoxy-phenyl)-[1,4]thiazepan-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(2,4-dimethoxy-phenyl)-4-(2,2,2-trifluoro-ethanoyl)-[1,4]thiazepan-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   1-[7-(2,4-dimethoxy-phenyl)-5-(3-fluoro-4-methoxyphenyl)-[1,4]thizepan-4-yl]-ethanone;    -   4-hydroxy-6-methyl-3-[7-(3-phenyl-1H-pyrazol4-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   3-[7-(5-ethyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(1-benzyl-1H-indol-3-yl)-2,3,6,7-tetrahydro-[1        ,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   4-hydroxy-6-methyl-3[7-(2-trifluoromethylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   4-hydroxy-6-methyl-3[7-(3-trifluoromethylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   4-hydroxy-6-methyl-3[7-(4-trifluoromethylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   4-hydroxy-6-methyl-3-[7-[3-(3-trifluoromethyl-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   3-[7-[3-(3,4-dichloro-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-[3-(3,5-dichloro-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   4-hydroxy-6-methyl-3-{7-[5-(3-trifluoromethyl-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl        }-pyran-2-one;    -   3-{7-[5-(2-chloro-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;    -   3-{7-[5-(3-chloro-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;    -   3-{7-[5-(4-chloro-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;    -   4-hydroxy-6-methyl-3-{7-[5-(chloro-trifluoromethyl-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-pyran-2-one;    -   3-[7-(4-bromo-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(5-bromo-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(1-benzenesulfonyl-1H-pyrrol-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   4-hydroxy-6-methyl-3-[7-(3-methyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   4-hydroxy-6-methyl-3-[7-(5-methyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   4-hydroxy-6-methyl-3-[7-(1-methyl-1H-indol-3-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   3-[7-(chloro-methyl-trifluoromethyl-1H-pyrazol-4-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-{7-[1-(2,4-difluoro-benzenesulfonyl)-1H-pyrrrol-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl        }4-hydroxy-6-methyl-pyran-2-one;    -   3-(7-[2,2′]bithienyl-5-yl-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl)-4-hydroxy-6-methyl-pyran-2-one;    -   3-{7-[1-(3,5-dichloro-phenyl)-1H-pyrrrol-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl        }-4-hydroxy-6-methyl-pyran-2-one;    -   3-{7-[1-(4-chloro-phenyl)-1H-pyrrrol-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl        }-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(5-chloro-1H-indol-3-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   4-hydroxy-6-methyl-3-[7-(6-p-tolylsulfanyl-imidazo[2,1-b]thiazol-5-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   3-[7-(4,5-dibromo-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(2-chloro-5-trifluoromethyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one;    -   4-hydroxy-6-methyl-3-[7-(5-methylsulfanyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   3-[7-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[4-(2,4-dimethoxy-phenyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(4-dimethylamino-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-1H-quinolin-2-one;    -   4-hydroxy-6-methyl-3-[7-(4-trifluoromethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   3-[7-(bis-trifluoromethyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(4-dimethylamino-2-methoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-hydroxy-2-[2-(2,4-diethoxy-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-cyclohex-2-enone;    -   3-[7-(2,4-dimethoxy-phenyl)-1-oxo-2,3,6,7-tetrahydro-1H-1λ⁴-[1,4]thiazepin-5-yl]-4-hydroxy-6-methoxy-pyran-2-one;    -   10-(2,4-dimethoxy-phenyl)-3-methyl-7,8-dihydro-10H-2,5-dioxa-9-thia-6a-aza-cyclohepta[a]naphthalene-1,6-dione;    -   3-[7-(2,4-dimethoxy-phenyl)-1,1-dioxo-2,3,6,7-tetrahydro-1H-1λ⁶-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(2,4-diethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]4-hydroxy-6-methyl-pyran-2-one;    -   3-(7-[2,2′]bithienyl-5-yl-2,3-dihydro-[1,4]thiazepin-5-yl)-4-hydroxy-6-methyl-pyran-2-one;    -   2-[7-(2,4-diethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-3-hydroxy-cyclohex-2-enone;        and    -   3-[7-(2,4-diethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one.

A further preferred means for practicing any of the above methodscomprises administering a compound of Formula I, wherein said compoundis selected from the group consisting of:

-   -   4-hydroxy-6-methyl-3-[7-(4-methylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   3-[7-(4-ethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(3-methoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one;    -   3-[7-(2-bromo-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(2,3-dichloro-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]4-hydroxy-6-methyl-pyran-2-one;    -   3-[7-(3,4-dichloro-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   6-methyl-3-[7-(2,3,4-trimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   6-methyl-3-(2-p-tolyl-2,3-dihydro-benzo[b][1,4]thiazepin4-yl)-pyran-2-one;    -   4-hydroxy-6-methyl-3-[2-(4-methylsulfanyl-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-pyran-2-one.

A further preferred means for practicing any of the above methodscomprises administering a compound of Formula I, wherein said compoundis selected from the group consisting of:

-   -   4-hydroxy-6-methyl-3-[7-(4-methylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   3-[7-(3,4-dichloro-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;    -   6-methyl-3-[7-(2,3,4-trimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;    -   4-hydroxy-3-[7-(4-chloro-2-methoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methylpyran-2-one;        and    -   4-hydroxy-3-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one.        Chemistry

Processes for Making Compounds of the Invention

Compounds of the invention may be prepared by proceeding as in Scheme 1.

in which the dashed line indicates optional unsaturation, X⁴ is —NR² orSH, R¹² is —NHR² or —SH, R¹³ and R¹⁴ independently are hydrogen or anyof the optional substituents defined for A² in the Summary of theInvention or R¹³ and R¹⁴ together with the atoms to which R¹³ and R¹⁴are attached form a monocyclic or fused polycyclic ring system selectedfrom aryl containing a total of 6 to 9 ring atoms, heteroaryl containinga total of 5 to 9 ring atoms and unsaturated, partially unsaturated orsaturated carbocycloalkyl or heterocycloalkyl each containing a total of3 to 9 ring atoms and the compound of Formula 4 may be optionallysubstituted.

Compounds of the invention may be prepared by reacting a compound ofFormula 3 with a compound of Formula 4. The reaction is carried out in asuitable solvent (e.g., ethanol) at between 60 and 80° C. and requires10 minutes to 20 hours to complete. A detailed description for thepreparation of a compound of Formula I by the methods described above isset forth in Example 2, infra.

Compounds of Formula 3 can be prepared by reacting a ketone of Formula Iwith an aldehyde of Formula 2. The reaction is carried out in anappropriate solvent (e.g., ethanol) and in the presence of a suitablebase (e.g., piperidine) at between 80 to 85° C. and requires 8 to 24hours to complete. A detailed description for the preparation of acompound of Formula I by the methods described above is set forth inReference 5.1, infra.

Compounds of Formula I in which A² is [1,4]thiazepanylene wherein R¹ is—C(O)R⁶ can be prepared by reducing a compound of Formula I in which A²is 2,3,6,7-tetrahydro-[1,4]thiazepinylene to the correspondingthiazepane and then condensing the thiazepane with an anhydride of theFormula O[C(O)R⁶]₂. The reduction is carried out in a suitable solvent(e.g., ethanol) and in the presence of a suitable reducing agent (e.g.,sodium borohydride) at 35 and 50° C. and requires 0.5 to 6 hours tocomplete. The condensation reaction is carried out in the presence ofsuitable base (e.g., diisopropylethylamine (DIPEA)) and requires 0.5 to14 hours to complete. A detailed description for the preparation of acompound of Formula I by the methods described above is set forth inExample 1, infra.

Compounds of Formula I in which A² is1-oxo-2,3,6,7-tetrahydro-1H-1H1λ⁴-[1,4]thiazepinylene can be prepared byoxidizing a compound of Formula I in which A² is2,3,6,7-tetrahydro-[1,4]thiazepinylene. The oxidation is carried out ina suitable solvent (e.g., acetic acid) and in the presence of a suitableoxidizing agent (e.g., hydrogen peroxide) at ambient temperature andrequires 2 to 3 hours to complete. Compounds of Formula I in which A² is1,1-dioxo-2,3,6,7-tetrahydro-1H-1λ⁴-[1,4]thiazepinylene can be preparedby proceeding as described above, but heating the reaction atapproximately 70° C. for 2 to 3 hours. Detailed descriptions for thepreparation of a compound of Formula I by the methods described aboveare set forth in Examples 3 and 5, infra.

Compounds of Formula I in which A² is [1,4]thiazepanylene wherein R¹ andA¹ and the atoms to which A¹ and R¹ are attached together with A² form agroup of Formula (h) can be prepared by reacting a correspondingcompound of Formula I in which A² is2,3,6,7-tetrahydro-[1,4]thiazepinylene and A¹ is4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl with phosgene. The reaction iscarried out in a suitable solvent (e.g., ethylene dichloride) and in thepresence of a suitable acylation catalyst (e.g.,4-(dimethylamino)pyridine) and in the presence of suitable base (e.g.,DIPEA) at ambient temperature and requires 0.5 to 1 hours to complete. Adetailed description for the preparation of a compound of Formula I bythe methods described above is set forth in Example 4, infra.

Compounds of Formula I in which A² is 2,3-dihydro-[1,4]thiazepinylenecan be prepared by dehydrogenation of a corresponding compound ofFormula I in which A² is 2,3,6,7-tetrahydro-[1,4]thiazepinylene. Thereaction is carried out in a appropriate solvent (e.g., toluene) and inthe presence of a suitable catalyst (e.g.,2,3-dichloro-5,6-dicyano-1,4-benzoquinone) at 60 to 80° C. and requires20 to 30 minutes to complete. A detailed description for the preparationof a compound of Formula I by the methods described above is set forthin Example 5, infra.

EXPERIMENTALS Reference 13-Acetyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one

4-Hydroxy-6-methyl-5,6-dihydro-pyran-2-one (2 g, 15.6 mmol) was combinedwith methylene chloride (50 mL) in a 250 mL flask and then acetic acid(17.5 M, 2 eq, 31 mmol, 1.77 mL) was added to the mixture. The mixturewas cooled in an ice bath and then dicyclohexylcarbodiimide (1.3 eq,20.3 mmol, 4.19 g) was added portionwise, followed by the addition of4-(dimethylamino)pyridine (0.05 eq, 0.78 mmol, 88 mg) to the mixture. Asufficient amount of methylene chloride was added to ensure easystirring and the reaction was monitored by TLC (silica gel, hexane-ethylacetate-methylene chloride-acetone (3:3:3:1 v/v)), HPLC and LCMS as theintermediate acetic acid 2-methyl-6-oxo-3,6-dihydro-2H-pyran-4-yl esterwas formed. The mixture was stirred overnight at room temperature andthen toluene (20 ml) was added. The mixture was heated to 60° C. andafter 48 hours the mixture was filtered, concentrated and purified byflash column chromatography to provide3-acetyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one (1.02 g, 38%) as awhite solid, mp 96-98° C. (lit., mp 97-98° C.). LCMS: MH⁺ 171.0.

Reference 2 2-Acetyl-3-hydroxy-cyclohex-2-enone

3-Hydroxy-cyclohex-2-enone (1.08 g, 9.64 mmol) was combined withmethylene chloride (10 mL) in a 250 mL flask and acetic acid (1.4 eq,13.75 mmol, 0.78 mL) was added to the mixture. The mixture was cooled inan ice bath and dicyclohexylcarbodiimide (1.3 eq, 12 mmol, 2.5 g) wasadded portionwise, followed by the addition of 4-(dimethylamino)pyridine(0.05 eq, 0.45 mmol, 50 mg). A sufficient amount of methylene chloridewas added to ensure easy stirring and the reaction was monitored by TLC(silica gel, hexane-ethyl acetate-methylene chloride-acetone (3:3:3:1v/v)), HPLC and LCMS and the intermediate acetic acid3-oxo-cyclohex-1-enyl ester was formed. The mixture was stirredovernight at room temperature and then toluene (20 mL) was added. Themixture heated to 60° C. and after 72 hours the mixture was filtered,concentrated and purified by flash column chromatography to provide2-acetyl-3-hydroxy-cyclohex-2-enone (1.19 g, 80%) as a colorless liquid.LCMS: MH⁺ 154.8.

Reference 3 3-Acetyl-4-hydroxy-1H-quinolin-2-one

A solution of 2-amino-benzoic acid methyl ester (1.51 g, 10 mmol) andtriethylamine (97.2 mmol/ml, 0.0194 mL, 0.14 mmol, 0.014 eq) in toluene(4 mL) was heated to 60° C. and then a solution of4-methylene-oxetan-2-one (0.84 g, 10 mmol) in toluene (2 ml) was addedto the solution over 15 minutes. The reaction was heated at 80° C. for 6hours and then at 50° C. for 16 hours. Progress of the reaction wasmonitored by TLC (silica gel, hexane-ethyl acetate (7:3 v/v)),analytical HPLC and LCMS and upon its completion the mixture waspartitioned between ethyl acetate and aqueous hydrochloric acid (1 N).The organic layer was washed with water, saturated sodium bicarbonate,water and then brine, dried over Na₂SO₄ and concentrated to give anorange solid. The solid was crystalized from methylene chloride/ethylacetate and hexane to provide 2-(3-oxo-butanoylamino)-benzoic acidmethyl ester (1.83 g, 78%) as large colorless prisms, mp 81-83° C.(lit., mp 79-80° C.). LCMS MH⁺ 235.6.

2-(3-Oxo-butanoylamino)-benzoic acid methyl ester (383 mg, 1.63 mmol)was combined with diethyl ether (10 mL) and methanol (5 mL) and themixture was stirred rapidly while a solution of sodium methoxide (25%solution, 1.63 mmol, 0.45 mL) in methanol (3 mL) was added over 10minutes. The reaction then was heated at 40° C. overnight. Progress ofthe reaction was monitored by TLC (silica gel,hexane:EtOAc:CH₂Cl₂:acetone (3:3:3:1)) and analytical HPLC and upon itscompletion the mixture was acidified with 1 N sulfuric acid to form asolid. The solid was collected by filtration and then crystallized fromhot acetic acid/acetonitrile/water to provide3-acetyl-4-hydroxy-1H-quinolin-2-one (250 mg, 76%) as small colorlessprisms, mp 258-262° C. (dec) (lit., 259° C.). LCMS MH⁺ 204.2.

Reference 4 2-Methoxy4-methylsulfanyl-benzaldehyde

2-Methoxy-4-methylsulfanyl-benzoic acid (2 g, 10.09 mmol) was dissolvedin dry THF (20 mL) and the solution was stirred while heated to 60° C.under nitrogen and then borane-methylsulfide complex (1.7 eq, 1.7 mL,17.5 mmol) was added very slowly dropwise via a syringe. The progress ofthe reaction was followed by both TLC and analytical HPLC and whencomplete (3 hours) the mixture was allowed to cool to room temperature,diluted with water (10 mL) added extremely slowly dropwise undernitrogen. Potassium carbonate (1 g) was added and after stirring themixture for 30 minutes ethyl acetate (50 ml) was added. The organiclayer was separated, washed with water, 2 N hydrochloric acid, water andbrine, dried over Na₂SO₄ and then concentrated to a near colorless oil.The residue was triturated with hexane and product was purified from theresulting crystals by flash column chromatography to provide(2-methoxy-4-methylsulfanyl-phenyl)-methanol (934 mg, 51%) as colorlesscrystals. LCMS: M⁻182.8.

Pyridine (4.8 mL, 60 mmol, 12 eq) was added under nitrogen to a mixtureof chromium trioxide (fresh, 2 g, 20 mmol) in dry methylene chloride (15mL) cooled over an ice bath. The mixture was stirred at 0° C. for 1 hourand Celite powder (1 g) and a solution of(2-methoxy-4-methylsulfanyl-phenyl)-methanol (934 mg, 5.07 mmol) inmethylene chloride (10 mL) was added. The progress of the reaction wasfollowed by TLC (silica gel, hexane-EtOAc-CH₂Cl₂-acetone (3:3:3:1 v/v)and hexane-ethyl acetate (7:3 v/v)) and analytical HPLC and whencomplete, the mixture was applied to a silica gel column (made up inhexane) and the column eluted with methylene chloride. Pure fractionswere combined and concentrated to provide2-methoxy-4-methylsulfanyl-benzaldehyde (730 mg, 79%). LCMS: MH⁺ 183.2.

Reference 53-[7-(2,4-Dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one

Step 5.1

3-Acetyl-4-hydroxy-6-methyl-pyran-2-one (5.07 g, 30.15 mmol) and2,4-dimethoxybenzaldehyde (5.03 g, 30.27 mmol) were combined in a 250 mLround bottom flask. Absolute ethanol (20 mL) and piperidine (0.10 eq,0.30 mL, 3.0 mmol) were added and the mixture heated to between 80 and85 ° C. The reaction was monitored by TLC (silica gel, hexane-ethylacetate (1:1 v/v) and methylene chloride-ethyl acetate-acetone (5:5:1v/v)) and analytical HPLC. After 20 hours (>95% completion) the reactionmixture was cooled to room temperature to provide3-[3-(2,4-dimethoxy-phenyl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one asa bright orange crystalline precipitate. MS M⁺317. NMR (CDCl₃-TMS): d8.31 (m, 2H), 7.69 (d, 1H, J=9 Hz), 6.54 (d, 1H, J=9 Hz), 6.45 (s, 1H),5.93 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 2.26 (s, 3H) NMR (DMSO-d₆): d8.11 (s, 2H), 7.62 (d, 1H, J=9 Hz), 6.63 (bs, 2H), 6.23 (s, 1H), 3.87(s, 3H), 3.82 (s, 3H), 2.28 (s, 3H).

Step 5.2

The crude reaction mixture prepared in Step 5.1 was diluted withabsolute ethanol (5 mL). 2-Aminoethanethiol (2.31 g, 30 mmol fresh drymaterial) was added and the mixture heated to 75° C. The reaction wasmonitored by TLC (silica gel, hexane-ethyl acetate (1:1 v/v) andmethylene chloride-ethyl acetate-acetone (5:5:1 v/v)) and analyticalHPLC. After 1.5 hours (>90% completion) the reaction was allowed to coolto room temperature to form a yellow crystalline solid. The solidmaterial was collected by filtration and washed with ethanol-diethylether (1:1 v/v) and then hexane. Product was purified by columnchromatography and then crystallization (methylene chloride-ethanol) toprovide3-[7-(2,4-dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(6.81 g, 61%). LCMS: MH⁺375.6. Elemental Analysis: Calc: C 60.78, H5.64, N 3.73 Found: 60.73, H 5.66, N 3.73. ¹H NMR (CDCl₃-TMS): d 14.3(bs, 1H), 7.23 (m, 1H), 6.46 (m, 2H), 5.69 (s, 1H), 4.76 (d, 1H, J=13Hz), 4.47 (d, 1H, J=11 Hz), 4.17 (m, 1H), 4.00 (m, 1H), 3.83 (s, 3H),3.79 (s, 3H), 3.52 (t, 1H, J=11.5 Hz), 3.00 (t, 1H, J=11.5 Hz), 2.78(dd, 1H, J=11.5,5 Hz), 2.09 (s, 3H). ¹H NMR (DMSO-d₆): d 13.7 (bs, 1H),7.23 (dd, 1H, J=9, 3 Hz), 6.5 (m, 2H), 5.7 (s, 1H), 4.37 (d, 1H, J=13Hz), 4.28 (d, 1H, J=10 Hz), 4.08 (m, 2H), 3.73 (s, 6H), 3.61 (t, 1H,J=11 Hz), 2.79 (m, 2H), 2.03 (s, 3H). ¹³C NMR JEOL, (DMSO-d₆): d 183.84,178.36, 163.42, 162.89, 160.32, 157.33, 128.28, 123.29, 107.76, 105.46,99.16, 95.78, 56.26, 55.77, 46.0, 38.90, 34.19, 29.07, 19.68.

Proceeding as in Reference 5, Step 5.1, but substituting3-acetyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one for3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided3-[(E)-3-(2,4-dimethoxy-phenyl)-acryloyl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting2-acetyl-3-hydroxy-cyclohex-2-enone for3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided2-[3-(2,4-dimethoxy-phenyl)-acryloyl]-3-hydroxy-cyclohex-2-enone.

Proceeding as in Reference 5, Step 5.1, but substituting3-acetyl-4-hydroxy-1H-quinolin-2-one for3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided3-[(E)-3-(2,4-dimethoxy-phenyl)-acryloyl]-4-hydroxy-1H-quinolin-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting2-methoxy-4-methylsulfanyl-benzaldehyde for 2,4-dimethoxybenzaldehyde,provided4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5. 1, but substituting3-phenyl-1H-pyrazole-4-carbaldehyde for 2,4-dimethoxybenzaldehyde,provided4-hydroxy-6-methyl-3-[(E)-3-(3-phenyl-1H-pyrazol-4-yl)-acryloyl]-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting3-acetyl-4-methoxy-6-methyl-pyran-2-one for3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided3-[(E)-3-(2,4-dimethoxy-phenyl)-acryloyl]4-methoxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting5-ethylthiene-2-carbaldehyde for 2,4-dimethoxybenzaldehyde, provided3-[(E)-3-(5-ethyl-thien-2-yl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting1-benzyl-1H-indole-3-carbaldehyde for 2,4-dimethoxybenzaldehyde,provided3-[(E)-3-(1-benzyl-1H-indol-3-yl)acryloyl]-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5. 1, but substituting2-trifluormethylsulfanyl-benzaldehyde for 2,4-dimethoxybenzaldehyde,provided4-hydroxy-6-methyl-3-[(E)-3-(2-trifluoromethylsulfanyl-phenyl)-acryloyl]-pyran-2-one.

Proceeding as in Reference 5, Step 5. 1, but substituting3-trifluoromethylsulfanyl-benzaldehyde for 2,4-dimethoxybenzaldehyde,provided4-hydroxy-6-methyl-3-[(E)-3-(3-trifluoromethylsulfanyl-phenyl)-acryloyl]-pyran-2-one.

Proceeding as in Reference 5, Step 5. 1, but substituting4-trifluoromethylsulfanyl-benzaldehyde for 2,4-dimethoxybenzaldehyde,provided4-hydroxy-6-methyl-3-[(E)-3-(4-trifluoromethylsulfanyl-phenyl)-acryloyl]-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting3-(3-trifluoromethyl-phenoxy)-benzaldehyde for2,4-dimethoxybenzaldehyde, provided4-hydroxy-6-methyl-3-{(E)-3-[3-(3-trifluoromethyl-phenoxy)-phenyl]-acryloyl}-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting3-(3,4-dichloro-phenoxy)-benzaldehyde for 2,4-dimethoxybenzaldehyde,provided3-{(E)-3-[3-(3,4-dichloro-phenoxy)-phenyl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5. 1, but substituting3-(3,5-dichloro-phenoxy)-benzaldehyde for 2,4-dimethoxybenzaldehyde,provided3-{(E)-3-[3-(3,5-dichloro-phenoxy)-phenyl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting5-(3-trifluoromethyl-phenyl)-furan-2-carbaldehyde for2,4-dimethoxybenzaldehyde, provided4-hydroxy-6-methyl-3-{(E)-3-[5-(3-trifluoromethyl-phenyl)-furan-2-yl]-acryloyl}-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting5-(2-chloro-phenyl)-furan-2-carbaldehyde for 2,4-dimethoxybenzaldehyde,provided3-{(E)-3-[5-(2-chloro-phenyl)-furan-2-yl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but5-(3-chloro-phenyl)-furan-2-carbaldehyde substituting for2,4-dimethoxybenzaldehyde, provided3-{(E)-3-[5-(3-chloro-phenyl)-furan-2-yl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting5-(4-chloro-phenyl)-furan-2-carbaldehyde for 2,4-dimethoxybenzaldehyde,provided3-{(E)-3-[5-(4-chloro-phenyl)-furan-2-yl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting5-(chloro-trifluoromethyl-phenyl)-furan-2-carbaldehyde for2,4-dimethoxybenzaldehyde, provided3-{(E)-3-[5-(chloro-trifluoromethyl-phenyl)-furan-2-yl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting4-bromo-thiene-2-carbaldehyde for 2,4-dimethoxybenzaldehyde, provided3-[(E)-3-(4-bromo-thien-2-yl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting5-bromo-thiene-2-carbaldehyde for 2,4-dimethoxybenzaldehyde, provided3-[(E)-3-(5-bromo-thien-2-yl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but1-benzenesulfonyl-1H-pyrrole-2-carbaldehyde substituting for2,4-dimethoxybenzaldehyde, provided3-[(E)-3-(1-benzenesulfonyl-1H-pyrrol-2-yl)-acryloyl]-4-hydroxy-6-methy-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting3-methyl-thiene-2-carbaldehyde for 2,4-dimethoxybenzaldehyde, provided4-hydroxy-6-methyl-3-[(E)-3-(3-methyl-thien-2-yl)-acryloyl]-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting5-methyl-thiene-2-carbaldehyde for 2,4-dimethoxybenzaldehyde, provided4-hydroxy-6-methyl-3-[(E)-3-(5-methyl-thien-2-yl)-acryloyl]-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting1-methyl-1H-indole-3-carbaldehyde for 2,4-dimethoxybenzaldehyde,provided4-hydroxy-6-methyl-3-[(E)-3-(1-methyl-1H-indol-3-yl)-acryloyl]-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substitutingchloro-methyl-trifluoromethyl-1H-pyrazole-4-carbaldehyde for2,4-dimethoxybenzaldehyde, provided3-[(E)-3-(chloro-methyl-trifluoromethyl-1H-pyrazol-4-yl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting1-(2,4-difluoro-benzenesulfonyl)-1H-pyrrole-2-carbaldehyde for2,4-dimethoxybenzaldehyde, provided3-{(E)-3-[1-(2,4-difluoro-benzenesulfonyl)-1H-pyrrol-2-yl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting[2,2′]bithienyl-5-carbaldehyde for 2,4-dimethoxybenzaldehyde, provided3-((E)-3-[2,2′]bithienyl-5-yl-acryloyl)-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting1-(3,5-dichloro-phenyl)-1H-pyrrole-2-carbaldehyde for2,4-dimethoxybenzaldehyde, provided3-{(E)-3-[1-(3,5-dichloro-phenyl)-1H-pyrrol-2-yl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting1-(4-chloro-phenyl)-1H-pyrrole-2-carbaldehyde for2,4-dimethoxybenzaldehyde, provided3-{(E)-3-[1-(4-chloro-phenyl)-1H-pyrrol-2-yl]-acryloyl}-4-hydroxy-6-methy-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting5-chloro-1H-indole-3-carbaldehyde for 2,4-dimethoxybenzaldehyde,provided3-[(E)-3-(5-chloro-1H-indol-3-yl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting6-p-tolylsulfanyl-imidazo[2,1-b]thiazole-5-carbaldehyde for2,4-dimethoxybenzaldehyde, provided4-hydroxy-6-methyl-3-[(E)-3-(6-p-tolylsulfanyl-imidazo[2,1-b]thiazol-5-yl)-acryloyl]-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting4,5-dibromo-thiene-2-carbaldehyde for 2,4-dimethoxybenzaldehyde,provided3-[(E)-3-(4,5-dibromo-thien-2-yl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substitutingchloro-trifluoromethyl-benzaldehyde for 2,4-dimethoxybenzaldehyde,provided3-[(E)-3-(chloro-trifluoromethyl-phenyl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting3-acetyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one for3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided3-[(E)-3-(2,4-dimethoxy-phenyl)-acryloyl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting5-methylsulfanyl-thiene-2-carbaldehyde for 2,4-dimethoxybenzaldehyde,provided4-hydroxy-6-methyl-3-[(E)-3-(5-methylsulfanyl-thien-2-yl)-acryloyl]-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting5-chloro-1-methyl-3-phenyl-1H-pyrazole-4-carbaldehyde for2,4-dimethoxybenzaldehyde, provided3-[(E)-3-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-yl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting2-acetyl-3-hydroxy-cyclohex-2-enone for3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided2-[3-(2,4-dimethoxy-phenyl)-acryloyl]-3-hydroxy-cyclohex-2-enone.

Proceeding as in Reference 5, Step 5.1, but substituting1-(3-fluoro-4-methoxy-phenyl)-ethanone for3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided(E)-1-(3-fluoro-4-methoxy-phenyl)-3-(2-hydroxy-4-methoxy-phenyl)-propenone.

Proceeding as in Reference 5, Step 5.1, but substituting4-dimethylamino-benzaldehyde for 2,4-dimethoxybenzaldehyde, provided3-[(E)-3-(4-dimethylamino-phenyl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting3-acetyl-4-hydroxy-1H-quinolin-2-one for3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided3-[(E)-3-(2,4-dimethoxy-phenyl)-acryloyl]-4-hydroxy-1H-quinolin-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting4-trifluoromethoxy-benzaldehyde for 2,4-dimethoxybenzaldehyde, provided4-hydroxy-6-methyl-3-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substitutingbis-trifluoromethyl-benzaldehyde for 2,4-dimethoxybenzaldehyde, provided3-[(E)-3-(bis-trifluoromethyl-phenyl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting4-dimethylamino-2-methoxy-benzaldehyde for 2,4-dimethoxybenzaldehyde,provided3-[(E)-3-(4-dimethylamino-2-methoxy-phenyl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting4-methanesulfonyl-benzaldehyde for 2,4-dimethoxybenzaldehyde, provided4-hydroxy-3-[(E)-3-(4-methanesulfonyl-phenyl)-acryloyl]-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting2,4-diethoxy-benzaldehyde for 2,4-dimethoxybenzaldehyde, provided3-[(E)-3-(2,4-diethoxy-phenyl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting2,4-diethoxy-benzaldehyde for 2,4-dimethoxybenzaldehyde and3-acetyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one for3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided3-[(E)-3-(2,4-diethoxy-phenyl)-acryloyl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting4-dimethylamino-benzaldehyde for 2,4-dimethoxybenzaldehyde and3-acetyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one for3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided3-[(E)-3-(4-dimethylamino-phenyl)-acryloyl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting2,4-diethoxy-benzaldehyde for 2,4-dimethoxybenzaldehyde and2-acetyl-3-hydroxy-cyclohex-2-enone for3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided2-[(E)-3-(2,4-diethoxy-phenyl)-acryloyl]-3-hydroxy-cyclohex-2-enone.

Proceeding as in Reference 5, Step 5.1, but substituting2,4-diethoxy-benzaldehyde for 2,4-dimethoxybenzaldehyde and2-acetyl-3-hydroxy-cyclohex-2-enone for3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided2-[(E)-3-(2,4-diethoxy-phenyl)-acryloyl]-3-hydroxy-cyclohex-2-enone.

Proceeding as in Reference 5, Step 5.1, but substituting2,3,4-trimethoxy-benzaldehyde for 2,4-dimethoxybenzaldehyde and2-acetyl-3-hydroxy-cyclohex-2-enone for3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided3-hydroxy-2-[(E)-3-(2,3,4-trimethoxy-phenyl)-acryloyl]-cyclohex-2-enone.

Proceeding as in Reference 5, Step 5.1, but substituting2-methoxy-4-methylsulfanyl-benzaldehyde for 2,4-dimethoxybenzaldehyde,provided4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one.

Proceeding as in Reference 5, Step 5.1, but substituting2,3,4-timethoxy-benzaldehyde for 2,4-dimethoxybenzaldehyde and3-acetyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one for3-acetyl-4-hydroxy-6-methyl-pyran-2-one, provided4-hydroxy-6-methyl-3-[(E)-3-(2,3,4-trimethoxy-phenyl)-acryloyl]-5,6-dihydro-pyran-2-one.

Example 13-[4-Acetyl-7-(2,4-dimethoxy-phenyl)-[1,4]thiazepan-5-yl]-4-hydroxy-6-methyl-pyran-2-oneCompound 1

3-[7-(2,4-Dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(187 mg, 0.5 mmol), prepared as in Reference 5, was combined withabsolute ethanol (5 mL) and sodium borohydride (20 mg, 0.526 mmol) andthe mixture was warmed on a hot plate to form a solution. The progressof the reaction was followed by analytical HPLC and LCMS and whencomplete (5 hours) acetic anhydride (1.5 ml. 30 eq) and DIPEA (0.6 mmol,0.1 mL) were added. The reaction was stirred at room temperatureovernight. Product was isolated by preparative HPLC (RPC₁₈ column,acetonitrile/water containing 0.1% HCl) to provide3-[4-acetyl-7-(2,4-dimethoxy-phenyl)-[1,4]thiazepan-5-yl]-4-hydroxy-6-methyl-pyran-2-one(25 mg). LCMS: MH⁺ 420.2.

Proceeding as in Example 1, but substituting trifluoroacetic anhydridefor acetic anhydride, provided3-[7-(2,4-dimethoxy-phenyl)-4-(2,2,2-trifluoro-ethanoyl)-[1,4]thiazepan-5-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 2); LCMS: MH⁺ 474.0.

Proceeding as in Example 1, but substituting7-(2,4-dimethoxy-phenyl)-5-(3-fluoro-4-methoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepinefor3-[7-(2,4-dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one,provided1-[7-(2,4-dimethoxy-phenyl)-5-(3-fluoro-4-methoxy-phenyl)-[1,4]thiazepan4-yl]-ethanone(Compound 3); LCMS: MH⁺ 420.2.

Example 24-Hydroxy-3-[7-(2-methoxy-4-methylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-oneCompound 4

4-Hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one(41.8 mg, 0.126 mmol), prepared as in Reference 5, Step 5.1, wasdissolved in absolute ethanol (5 mL) and then 2-aminoethanethiol (9.8mg, 0.126 mmol) was added to the solution. The mixture was stirred at80° C. The progress of the reaction was followed by analytical HPLC andwhen complete (approximately 12 hours) the solvent was removed in vacuo.Product was purified by silica flash column chromatography to provide4-hydroxy-3-[7-(2-methoxy-4-methylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one(20.5 mg) as a pale, yellow solid. LCMS: MH⁺ 392.6.

Proceeding as in Example 2, but substituting4-hydroxy-6-methyl-3-[(E)-3-(3-phenyl-1H-pyrazol-4-yl)-acryloyl]-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided4-hydroxy-6-methyl-3-[7-(3-phenyl-1H-pyrazol-4-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one(Compound 5); LCMS: MH⁺ 383.

Proceeding as in Example 2, but substituting3-[(E)-3-(2,4-dimethoxy-phenyl)-acryloyl]-4-methoxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]4-methoxy-6-methyl-pyran-2-one(Compound 6); MS MH⁺ 390.

Proceeding as in Example 2, but substituting3-[(E)-3-(5-ethyl-thien-2-yl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(5-ethyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 7); LCMS: MH⁺ 349.9.

Proceeding as in Example 2, but substituting3-[(E)-3-(1-benzyl-1H-indol-3-yl)acryloyl]-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(1-benzyl-1H-indol-3-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]4-hydroxy-6-methyl-pyran-2-one(Compound 8); LCMS: MH⁺ 445.2.

Proceeding as in Example 2, but substituting4-hydroxy-6-methyl-3-[(E)-3-(2-trifluoromethylsulfanyl-phenyl)-acryloyl]-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided4-hydroxy-6-methyl-3-[7-(2-trifluoromethylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one(Compound 9); LCMS: MH⁺ 416.4.

Proceeding as in Example 2, but substituting4-hydroxy-6-methyl-3-[(E)-3-(3-trifluoromethylsulfanyl-phenyl)-acryloyl]-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided4-hydroxy-6-methyl-3-[7-(3-trifluoromethylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one(Compound 10); LCMS: MH⁺ 416.6.

Proceeding as in Example 2, but substituting4-hydroxy-6-methyl-3-[(E)-3-(4-trifluoromethylsulfanyl-phenyl)-acryloyl]-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided4-hydroxy-6-methyl-3-[7-(4-trifluoromethylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one(Compound 11); LCMS: MH⁺ 416.5.

Proceeding as in Example 2, but substituting4-hydroxy-6-methyl-3-{(E)-3-[3-(3-trifluoromethyl-phenoxy)-phenyl]-acryloyl}-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided4-hydroxy-6-methyl-3-{7-[3-(3-trifluoromethyl-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-pyran-2-one(Compound 12); LCMS: MH⁺ 476.2.

Proceeding as in Example 2, but substituting3-{(E)-3-[3-(3,4-dichloro-phenoxy)-phenyl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-{7-[3-(3,4-dichloro-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one(Compound 13); LCMS: MH⁺ 475.8.

Proceeding as in Example 2, but substituting3-{(E)-3-[3-(3,5-dichloro-phenoxy)-phenyl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-{7-[3-(3,5-dichloro-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one(Compound 14); LCMS: MH⁺ 475.9.

Proceeding as in Example 2, but substituting4-hydroxy-6-methyl-3-{(E)-3-[5-(3-trifluoromethyl-phenyl)-furan-2-yl]-acryloyl}-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided4-hydroxy-6-methyl-3-{7-[5-(3-trifluoromethyl-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-pyran-2-one(Compound 15); LCMS: MH⁺ 450.1.

Proceeding as in Example 2, but substituting3-{(E)-3-[5-(2-chloro-phenyl)-furan-2-yl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-{7-[5-(2-chloro-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one(Compound 16); LCMS: MH⁺ 416.1.

Proceeding as in Example 2, but substituting3-{(E)-3-[5-(3-chloro-phenyl)-furan-2-yl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-{7-[5-(3-chloro-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one(Compound 17); LCMS: MH⁺ 416.1.

Proceeding as in Example 2, but substituting3-{(E)-3-[5-(4-chloro-phenyl)-furan-2-yl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-{7-[5-(4-chloro-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one(Compound 18); LCMS: MH⁺ 416.1.

Proceeding as in Example 2, but substituting3-{(E)-3-[5-(2-chloro-5-trifluoromethyl-phenyl)-furan-2-yl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-{7-[5-(2-chloro-5-trifluoromethyl-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one(Compound 19); LCMS: MH⁺ 483.9.

Proceeding as in Example 2, but substituting3-[(E)-3-(4-bromo-thien-2-yl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(4-bromo-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 20); LCMS: MH⁺ 401.8.

Proceeding as in Example 2, but substituting3-[(E)-3-(5-bromo-thien-2-yl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(5-bromo-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 21); LCMS: MH⁺ 401.8.

Proceeding as in Example 2, but substituting3-[(E)-3-(1-benzenesulfonyl-1H-pyrrol-2-yl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(1-benzenesulfonyl-1H-pyrrol-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 22); LCMS: MH⁺ 445.5.

Proceeding as in Example 2, but substituting4-hydroxy-6-methyl-3-[(E)-3-(3-methyl-thien-2-yl)-acryloyl]-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided4-hydroxy-6-methyl-3-[7-(3-methyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one(Compound 23); LCMS: MH⁺ 336.0.

Proceeding as in Example 2, but substituting4-hydroxy-6-methyl-3-[(E)-3-(5-methyl-thien-2-yl)-acryloyl]-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided4-hydroxy-6-methyl-3-[7-(5-methyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one(Compound 24); LCMS: MH⁺ 336.0.

Proceeding as in Example 2, but substituting4-hydroxy-6-methyl-3-[(E)-3-(1-methyl-1H-indol-3-yl)-acryloyl]-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided4-hydroxy-6-methyl-3-[7-(1-methyl-1H-indol-3-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one(Compound 25); LCMS: MH⁺ 369.2.

Proceeding as in Example 2, but substituting3-[(E)-3-(chloro-methyl-trifluoromethyl-1H-pyrazol4-yl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(chloro-methyl-trifluoromethyl-1H-pyrazol-4-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 26); LCMS: MH⁺ 421.8.

Proceeding as in Example 2, but substituting3-{(E)-3-[1-(2,4-difluoro-benzenesulfonyl)-1H-pyrrol-2-yl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-{7-[1-(2,4-difluoro-benzenesulfonyl)-1H-pyrrol-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one(Compound 28); LCMS: MH⁺ 480.8.

Proceeding as in Example 2, but substituting3-((E)-3-[2,2′]bithienyl-5-yl-acryloyl)-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-(7-[2,2′]bithienyl-5-yl-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl)-4-hydroxy-6-methyl-pyran-2-one(Compound 29); LCMS: MH⁺ 404.0.

Proceeding as in Example 2, but substituting3-{(E)-3-[l-(3,5-dichloro-phenyl)-1H-pyrrol-2-yl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-{7-[1-(3,5-dichloro-phenyl)-1H-pyrrol-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one(Compound 30); LCMS: MH⁺ 449.0.

Proceeding as in Example 2, but substituting3-{(E)-3-[1-(4-chloro-phenyl)-1H-pyrrol-2-yl]-acryloyl}-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-{7-[1-(4-chloro-phenyl)-1H-pyrrol-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one(Compound 31); LCMS: MH⁺ 415.2.

Proceeding as in Example 2, but substituting3-[(E)-3-(5-chloro-1H-indol-3-yl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(5-chloro-1H-indol-3-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 32); LCMS: MH⁺ 389.0.

Proceeding as in Example 2, but substituting4-hydroxy-6-methyl-3-[(E)-3-(6-p-tolylsulfanyl-imidazo[2,1-b]thiazol-5-yl)-acryloyl]-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided4-hydroxy-6-methyl-3-[7-(6-p-tolylsulfanyl-imidazo[2,1-b]thiazol-5-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one(Compound 33); LCMS: MH⁺ 484.4.

Proceeding as in example 2, but substituting3-[(E)-3-(4,5-dibromo-thien-2-yl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(4,5-dibromo-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 34); LCMS: MH⁺ 479.6.

Proceeding as in Example 2, but substituting3-[(E)-3-(2-chloro-5-trifluoromethyl-phenyl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(2-chloro-5-trifluoromethyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 35) 418.1.

Proceeding as in Example 2, but substituting3-[(E)-3-(2,4-dimethoxy-phenyl)-acryloyl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-onefor3-[3-(2,4-dimethoxy-phenyl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one,provided3-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one(Compound 36); MS M⁺378.0; NMR (CDCl₃-TMS): d 13.00 (bs, 1H), 7.2 (d,1H, J=9 Hz), 6.45 (m, 2H), 4.36 (d, 1H, J=9 Hz), 4.35 (m, 1H), 4.96-3.91(m, 2H), 3.84 (s, 3H), 3.8 (m, 1H), 3.78 (s, 3H), 3.52 (dd, 1H, J=10Hz), 2.98 (m, 1H), 2.77 (m, 1H), 2.55-2.36 (m, 2H), 1.35 (d, 3H, J=6.5Hz).

Proceeding as in Example 2, but substituting4-hydroxy-6-methyl-3-[(E)-3-(5-methylsulfanyl-thien-2-yl)-acryloyl]-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided4-hydroxy-6-methyl-3-[7-(5-methylsulfanyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one(Compound 37); LCMS: MH⁺ 367.4.

Proceeding as in Example 2, but substituting3-[(E)-3-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-yl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 38); LCMS: MH⁺ 430.0.

Proceeding as in Example 2, but substituting2-[3-(2,4-dimethoxy-phenyl)-acryloyl]-3-hydroxy-cyclohex-2-enone for3-[3-(2,4-dimethoxy-phenyl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one,provided2-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-3-hydroxy-cyclohex-2-enone(Compound 39); MS M⁺ 361.8.

Proceeding as in Example 2, but substituting benzene-1,2-diamine for2-aminoethanethiol, provided3-[4-(2,4-dimethoxy-phenyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 40); LCMS: MH⁺ 407.2.

Proceeding as in Example 2, but substituting3-[(E)-3-(4-dimethylamino-phenyl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(4-dimethylamino-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 42); MS M⁺ 359.0.

Proceeding as in Example 2, but substituting3-[(E)-3-(2,4-dimethoxy-phenyl)-acryloyl]-4-hydroxy-1H-quinolin-2-onefor3-[3-(2,4-dimethoxy-phenyl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one,provided3-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-1H-quinolin-2-one(Compound 43); MS M⁺ 411.0.

Proceeding as in Example 2, butsubstituting4-hydroxy-6-methyl-3-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided4-hydroxy-6-methyl-3-[7-(4-trifluoromethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one(Compound 44); MS M⁺ 399.8.

Proceeding as in Example 2, but substituting3-[(E)-3-(bis-trifluoromethyl-phenyl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(bis-trifluoromethyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 45); MS M⁺ 452.0.

Proceeding as in Example 2, but substituting3-[(E)-3-(4-dimethylamino-2-methoxy-phenyl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(4-dimethylamino-2-methoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 46); MS M⁺ 389.0.

Proceeding as in Example 2, but substituting4-hydroxy-3-[(E)-3-(4-methanesulfonyl-phenyl)-acryloyl]-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided4-hydroxy-3-[7-(4-methanesulfonyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one(Compound 47); MS M⁺ 393.8.

Proceeding as in Example 2, but substituting3-[(E)-3-(2,4-diethoxy-phenyl)-acryloyl]4-hydroxy-6-methyl-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-oneand 2-amino-benzenethiol for 2-aminoethanethiol, provided3-[2-(2,4-diethoxy-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 48); MS M⁺ 452.0.

Proceeding as in Example 2, but substituting3-[(E)-3-(2,4-diethoxy-phenyl)-acryloyl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one(Compound 49); MS M⁺ 406.2.

Proceeding as in Example 2, but substituting3-[(E)-3-(4-dimethylamino-phenyl)-acryloyl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-[7-(4-dimethylamino-phenyl)-2,3,6,7-tetrahydro-1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one(Compound 50); MS M⁺ 361.0.

Proceeding as in Example 2, but substituting2-[(E)-3-(2,4-diethoxy-phenyl)-acryloyl]-3-hydroxy-cyclohex-2-enone for4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided2-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-3-hydroxy-cyclohex-2-enone(Compound 51); MS M⁺ 390.0.

Proceeding as in Example 2, but substituting3-hydroxy-2-[(E)-3-(2,3,4-trimethoxy-phenyl)-acryloyl]-cyclohex-2-enonefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided3-hydroxy-2-[7-(2,3,4-trimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-cyclohex-2-enone(Compound 52); MS M⁺ 392.2.

Proceeding as in Example 2, but substituting2-[(E)-3-(2,4-diethoxy-phenyl)-acryloyl]-3-hydroxy-cyclohex-2-enone for4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-oneand 2-amino-benzenethiol for 2-aminoethanethiol, provided2-[2-(2,4-diethoxy-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-3-hydroxy-cyclohex-2-enone(Compound 53); MS M⁺ 438.4.

Proceeding as in Example 2, but substituting3-hydroxy-2-[(E)-3-(2,3,4-trimethoxy-phenyl)-acryloyl]-cyclohex-2-enonefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-oneand 2-amino-benzenethiol for 2-aminoethanethiol, provided3-hydroxy-2-[2-(2,3,4-trimethoxy-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-cyclohex-2-enone (Compound 54); MS M⁺ 439.8.

Proceeding as in Example 2, but substituting3-[3-(2,4-dimethoxy-phenyl)-acryloyl]-4-hydroxy-6-methyl-pyran-2-one for4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-oneand 2-amino-3-mercapto-3-methyl-butyric acid for 2-aminoethanethiol,provided7-(2,4-dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepine-3-carboxylicacid (Compound 55); MS M⁺ 448.0.

Proceeding as in Example 2, but4-hydroxy-6-methyl-3-[(E)-3-(2,3,4-trimethoxy-phenyl)-acryloyl]-5,6-dihydro-pyran-2-onesubstituted for4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-oneand 2-amino-benzenethiol for 2-aminoethanethiol, provided4-hydroxy-6-methyl-3-[2-(2,3,4-trimethoxy-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-5,6-dihydro-pyran-2-one(Compound 56); MS M⁺ 456.2.

Proceeding as in Example 2, but substituting4-hydroxy-6-methyl-3-[(E)-3-(2,3,4-trimethoxy-phenyl)-acryloyl]-5,6-dihydro-pyran-2-onefor4-hydroxy-3-[(E)-3-(2-methoxy-4-methylsulfanyl-phenyl)-acryloyl]-6-methyl-pyran-2-one,provided4-hydroxy-6-methyl-3-[7-(2,3,4-trimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-5,6-dihydro-pyran-2-one(Compound 57); MS M⁺ 408.4.

Example 33-[7-(2,4-Dimethoxy-phenyl)-1-oxo-2,3,6,7-tetrahydro-1H-1λ⁴-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-oneCompound 58

3-[7-(2,4-Dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(0.12 g, 0.32 mmol), prepared as in Reference 5, was dissolved in aceticacid (2 mL) and then hydrogen peroxide (0.3 ml, 35 wt % in water) wasadded at room temperature. The reaction was monitored by analyticalHPLC. After 2 hours the solvent was removed in vacuo. Product waspurified by preparative HPLC (RPC₁₈ column, 2-60% acetonitrile/watercontaining 0.1% HCl) to provide a diasteromeric mixture of3-[7-(2,4-dimethoxy-phenyl)-1-oxo-2,3,6,7-tetrahydro-1H-1λ⁴-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(4.4 mg) as a yellow powder. LCMS: MH⁺ 392.0.

Example 410-(2,4-Dimethoxy-phenyl)-3-methyl-7,8-dihydro-10H-2,5-dioxa-9-thia-6a-aza-cyclohepta[a]naphthalene-1,6-dioneCompound 59

3-[7-(2,4-Dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(63 mg, 0.168 mmol), prepared as in Reference 5, was dissolved inethylene dichloride (2 mL) and then 4-(dimethylamino)pyridine (0.020 g),di-iso-propylethylamine (0.5 mL) and phosgene (0.4 ml, 2 M in toluene)were added at room temperature. The reaction was monitored by analyticalHPLC. After stirring at room temperature for 30 minutes, the solvent wasremoved in vacuo. Product was purified by HPLC (RPC₁₈ column, 2-70%acetonitrile/water containing 0.1% HCl) to provide10-(2,4-dimethoxy-phenyl)-3-methyl-7,8-dihydro-10H-2,5-dioxa-9-thia-6a-aza-cyclohepta[a]naphthalene-1,6-dione(20 mg) as an off-white powder. LCMS: M⁺ 401.0.

Example 53-[7-(2,4-Dimethoxy-phenyl)-1,1-dioxo-2,3,6,7-tetrahydro-1H-1λ⁶[1,4]thiazepin-5-yl]4-hydroxy-6-methyl-pyran-2-oneCompound 60

3-[7-(2,4-Dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(190 mg, 0.5 mmol), prepared as in Reference 5, was dissolved in aceticacid (2 ml) and hydrogen peroxide (0.3 ml, 35 wt % in water) was addedto the solution at room temperature. The clear solution was stirred at70° C. The reaction was monitored by analytical HPLC. After 2 hours thesolvent was removed in vacuo. Product was purified by preparative HPLC(RPC₁₈ column, 2-60% acetonitrile/water containing 0.1% HCl) to provide3-[7-(2,4-dimethoxy-phenyl)-1,1-dioxo-2,3,6,7-tetrahydro-1H-1λ⁶[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(10 mg) as a yellow powder. LCMS: MH⁺ 408.0.

Example 63-[7-(2,4-Dimethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-oneCompound 61

3-[7-(2,4-Dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(150 mg, 0.39 mmol), prepared as in Reference 5, was dissolved intoluene (2 ml) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.3 mL, 35wt % in water) was added to the solution. The mixture was stirred at 80°C. The reaction was monitored by analytical HPLC and after reaction wascomplete (20 minutes) the solvent was then removed in vacuo. Product waspurified by preparative HPLC (RPC₁₈ column, 2-80% acetonitrile/watercontaining 0.1% HCl) to provide3-[7-(2,4-dimethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(35 mg) as an orange powder. LCMS: MH⁺ 373.0.

Proceeding as in Example 6, but substituting3-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-onefor3-[7-(2,4-dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one,provided3-[7-(2,4-diethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one(Compound 62); MS M⁺ 402.0.

Proceeding as in Example 6, but substituting3-(7-[2,2′]bithienyl-5-yl-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl)-4-hydroxy-6-methyl-pyran-2-onefor3-[7-(2,4-dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one,provided3-(7-[2,2′]bithienyl-5-yl-2,3-dihydro-[1,4]thiazepin-5-yl)-4-hydroxy-6-methyl-pyran-2-one(Compound 63); MS M⁺ 402.2.

Proceeding as in Example 6, but substituting2-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-3-hydroxy-cyclohex-2-enonefor3-[7-(2,4-dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one,provided2-[7-(2,4-diethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-3-hydroxy-cyclohex-2-enone(Compound 64); MS M⁺ 388.4.

Proceeding as in Example 6, but substituting3-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]4-hydroxy-6-methyl-5,6-dihydro-pyran-2-onefor3-[7-(2,4-dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one,provided3-[7-(2,4-diethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one (Compound 65); MS M⁺ 404.4.

Example 72-({1-[7-(2,4-Dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepin-3-yl]-methanoyl}-amino)-propionicacid tert-butyl ester Compound 66

7-(2,4-Dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepine-3-carboxylicacid (0.03 g), prepared as in Example 2, was dissolved in DMF (2 mL) and2-amino-propionic acid tert-butyl ester (0.012 g), N-methylmorpholine(0.2 ml) and PyBOP (0.034 g) were added to the solution at roomtemperature. The mixture was stirred while the progress of the reactionwas followed by analytical HPLC and when complete (16 hours) the solventwas removed in vacuo. Purification of product by preparative HPLC (RPC₁₈column, 2-70% acetonitrile/water containing 0.1% HCl) provided2-({1-[7-(2,4-dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepin-3-yl]-methanoyl}-amino)-propionic acid tert-butyl ester (18 mg) as an off-white powder.LCMS: M⁺ 575.0.

Proceeding by methods analogous to those described in the applicationthe following compounds can be made:

-   -   4-hydroxy-6-methyl-3-[7-(4-methylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one        (Compound 70),    -   3-[7-(4-ethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one        (Compound 71),    -   4-hydroxy-3-[7-(3-methoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one        (Compound 72),    -   3-[7-(2-bromo-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]4-hydroxy-6-methyl-pyran-2-one        (Compound 74),    -   3-[7-(3,4-dichloro-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one        (Compound 79),    -   3-[7-(2,3-dichloro-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one        (Compound 82),    -   4-hydroxy-6-methyl-3-[7-(2,3,4-trimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one        (Compound 83),    -   4-hydroxy-6-methyl-3-(2-p-tolyl-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl)-pyran-2-one        (Compound 85) and    -   4-hydroxy-6-methyl-3-[2-(4-methylsulfanyl-phenyl)-2,3-dihydro-benzo[b][1,4]thiazepin-4-yl]-pyran-2-one        (Compound 86).

Example 8 Identification of Caspase Cascade Activators and Inducers ofApoptosis in Solid Tumor Cells

Human breast cancer cell lines T-47D and ZR-75-1 were grown according tomedia component mixtures designated by American Type Culture Collection+10% fetal calf sera (FCS) (Life Technologies, Inc.) in a 5% CO₂-95%humidity incubator as 37° C. The T-47 and ZR-75-1 cells were maintainedat a cell density between 30 and 80% confluency at a cell density of 0.1to 0.6×10⁶ cells/mL. Cells were harvested at 600 xg and resuspended at0.65×10⁶ cells/mL into appropriate media +10% FCS. An aliquot of 45 μLof cells was added to a well of a 96-well microtiter plate containing 5μL of a 10% DMSO in RPMI-1640 media solution containing 1.6 to 100 μM oftest compound (0.16 to 10 μM final).

An aliquot of 45 μL of cells was added to a well of a 96-well microtiterplate containing 5 μL of a 10% DMSO in RPMI-1640 media solution withouttest compound as the control sample. The samples were mixed by agitationand then incubated at 37° C. for 24 hours in a 5% CO₂-95% humidityincubator. After incubation, the samples were removed from the incubatorand 50 μL of a solution w containing 20 μL ofN-(Ac-DEVD)-N′-ethoxycarbonyl-R110 (SEQ ID NO:1) fluorogenic substrate(Cytovia, Inc.; WO99/18856), 20% sucrose (Sigma), 20 mM dithiothreitol(DTT) (Sigma), 200 mM NaCl (Sigma), 40 mM Napiperazine-N,N′-bis[2-ethanesulfonic acid] (PIPES) buffer pH 7.2(Sigma), and 500 μg/mL lysolecithin (Calbiochem) was added. The sampleswere mixed by agitation and incubated at room temperature. Using afluorescent plate reader (Model 1420 Wallac Instruments), an initialreading (T=0) was made approximately 1-2 minutes after addition of thesubstrate solution, employing excitation at 485 nm and emission at 530nm, to determine the background fluorescence of the control sample.After the 3 hour incubation, the samples were read for fluorescence asabove (T=3 hours).

Calculation:

The Relative Fluorescence Unit (RFU) values were used to calculate thesample readings as follows:RFU_((T=3h))−Control RFU_((T=0))=Net RFU_((T=3h))

The level of caspase cascade activation was determined by the ratio ofthe net RFU value for the test compound to that of the control samples.The EC₅₀ (nM) was determined by a sigmoidal dose-response calculation(Prism 2.0, GraphPad Software, Inc.). The compounds of the inventionwere determined to have caspase cascade activating effects by proceedingas in Example 8.

TABLE I Caspase Potency EC₅₀ (nM) Compound # T-47D ZR-75-1 70  345  16372 3050 1950 74 3270 2080 79  557  349 85 6930 4207

Example 9 Identification of Antineoplastic Activity in CellProliferation

T-47D and ZR-75-1 cells are grown and harvested by proceeding as inExample 8. An aliquot of 90 μL of cells (2.2×10⁴ cells/mL) is added to awell of a 96-well microtiter plate containing 10 μL of a 10% DMSO inPRMI-1640 media solution containing 1 mM to 100 μM of test compound. Analiquot of 90 μL of cells is added to a well of a 96-well microtiterplate containing 10 μL of a 10% DMSO in RPMI-1640 media solution withouttest compound as the control sample for maximal cell proliferation(A_(max)). The samples are mixed by agitation and then incubated at 37°C. for 48 hours in a 5% CO₂-95% humidity incubator. After incubation,the samples are removed from the incubator and 20 μL of CellTiter 96Aqueous One Solution Cell Proliferation™ reagent (Promega) is added. Thesamples are mixed by agitation and incubated at 37° C. for 2-4 hours ina 5% CO₂-95% humidity incubator. Using an absorbance plate reader (Model1420 Wallac Instruments), an initial reading (T=0) is made approximately1-2 minutes after addition of the solution, employing absorbance at 490nm, to determine any background absorbance of the test compound. Afterthe 2-4 hours incubation, the samples are read for absorbance as above(A_(test)).

Baseline for the dose producing 50% inhibition of cell proliferation(GI₅₀) of initial cell numbers is determined by adding an aliquot of 90μL of cells or 90 μL of media, respectively, to wells of a 96-wellmicrotiter plate containing 10 μL of a 10% DMSO in RPMI-1640 mediasolution. The samples are mixed by agitation and then incubated at 37°C. for 0.5 hours in a 5% CO₂-95% humidity incubator. After incubation,the samples are removed from the incubator and 20 μL of CellTiter 96Aqueous One Solution Cell Proliferation™ reagent (Promega) is added. Thesamples are mixed by agitation and incubated at 37° C. for 2-4 hours ina 5% CO₂-95% humidity incubator. Absorbance is read as above, (A_(T=)0)defining absorbance for initial cell number used as baseline GI₅₀determinations.

Calculation:GI50(nM)=100×[A _(test) −A _(T=0)/(A _(max) −A _(T=0))].

Example 10 Nuclear Fragmentation in T47D Cells

T47D cells are grown and harvested by proceeding as in Example 8 andtreated with test compound followed by staining of the cell nuclei withSyto 16, a fluorescent DNA dye which stains nuclei. Shrunken andfragmented nuclei are hallmarks of caspase-mediated apoptosis. T47Dcells treated with test compound for 48 hours exhibit shrunken andfragmented nuclei.

Example 11 Mitotic Arrest in Jurkat Cells

Jurkat cells are incubated with a range of concentrations of testcompounds (0.02 μM to 5 μM) for 6 hours under normal growth conditions.Control cultures are treated with DMSO vehicle. The cells are thentreated for 20 minutes with 800 nM Syto 16. Cytospin preparation arethen prepared and the samples were viewed by fluorescent microscopyusing a fluorescein filter set. For each concentration of test compound,the number of mitotic figures are counted and expressed as a percentageof the total number of cells. Three fields from each condition areevaluated and the mean and SEM were calculated and plotted as a functionof drug concentration.

Example 12 Cell Cycle Arrest in Solid Tumor Cell Lines

T47D cells are grown and harvested by proceeding as in Example 8. Cellsat 1×10⁶ are treated with test compound for 48 hours at 37° C. As acontrol, cells are also incubated with DMSO. Cells were harvested at1200 rpm and washed twice with 5 mM EDTA/PBS. Cells are then resuspendedin 300 μL of EDTA/PBS and 700 mL of 100% ethanol, vortexed and incubatedat room temperature for 1 hour. Samples are spun down at 12000 rpm for 5minutes and the supernatant is removed. A solution containing 100 μg/mLof propidium iodide and 1 mg/mL of RNAse A (fresh) is added to thesamples and the samples are incubated for 1 hour at room temperature.Samples are then transferred to 12×75 mm polystyrene tubes and analyzedon a flow cytometer. All flow cytometry analyses are performed onFACScalibur (Becton Dickison) using Cell Quest analysis software.

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents, patent applications and publicationscited herein are fully incorporated by reference herein in theirentirety.

1. A compound of Formula I:

in which: the dashed lines indicate optional unsaturation withoutviolating valency rules; R¹ is hydrogen, (C₁₋₆)alkyl or —C(O)R⁶, whereinR⁶ is as defined below, or R¹ is absent when a double bond existsbetween the nitrogen atom to which R¹ is attached and an adjacent ringatom; X¹ is —S(O)_(n)—, wherein n is 0, 1, or 2; A¹ is a monocyclic orfused polycyclic ring system selected from aryl containing a total of 6to 14 ring atoms, heteroaryl containing a total of 5 to 14 ring atomsand unsaturated, partially unsaturated or saturated carbocycloalkyl orheterocycloalkyl each containing a total of 3 to 14 ring atoms, whereinA¹ may be substituted with a group selected from —X²R³, —X²OR³,—X²C(O)R³, —X²OC(O)R³, —X²C(O)OR³, —X²SR³, —X²S(O)R³, —X²S(O)₂R³,—X²NR³R⁴, —X²NR⁴C(O)R³, —X²NR⁴C(O)OR³, —X²C(O)NR³R⁴, —X²NR⁴C(O)NR³R⁴,—X²NR⁴C(NR⁴)NR³R⁴, —X²NR⁴S(O)₂R³ and —X²S(O)₂NR³R⁴, wherein X² is a bondor (C₁₋₆)alkylene, R³ is —X²R⁵ wherein X² is as defined above and R⁵ isaryl containing a total of 6 to 10 ring atoms, heteroaryl containing atotal of 5 to 10 ring atoms or unsaturated, partially unsaturated orsaturated carbocycloalkyl or heterocycloalkyl each containing a total of3 to 10 ring atoms, and R⁴ at each occurrence independently is hydrogen,(C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl, wherein each ring within A¹and R⁵ contains from 3 to 8 ring atoms and may be substituted with 1 to3 groups independently selected from (C₁₋₆)alkyl, cyano, halo, nitro,halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶, —X²C(O)OR⁴,—X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴, —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴,—X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴, —X²NR⁴C(NR⁴)NR⁴R⁴, —X²NR⁴S(O)₂R⁶ and—X²S(O)₂NR⁴R⁴, wherein X² and R⁴ are as defined above and R⁶ is(C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl, and wherein any saidcarbocycloalkyl and heterocycloalkyl rings within A¹ and R⁵ may besubstituted further with 1 to 2 groups independently selected from(C₁₋₆)alkylidene, oxo, imino and thioxo, with the proviso that only oneof A¹ and R⁵ is a fused polycyclic ring system; A²is a monocyclic ringselected from heteroarylene or unsaturated, partially unsaturated orsaturated heterocycloalkylene containing a total of 7 ring atoms,wherein A² may be substituted with a group selected from —X²R⁸, —X²OR⁸,—X²C(O)R⁸, —X²OC(O)R⁸, —X²C(O)OR⁸, —X²SR⁸, —X²S(O)R⁸, —X²S(O)₂R⁸,—X²NR⁴R⁸, —X²NR⁴C(O)R⁸, —X²NR⁴C(O)OR⁸, —X²C(O)NR⁴R⁸, —X²NR⁴C(O)NR⁴R⁸,—X²NR⁴C(NR⁴)NR⁴R⁸, —X²NR⁴S(O)₂R⁸ and —X²S(O)₂NR⁴R⁸, wherein X² is a bondor (C₁₋₆)alkylene, R⁸ is —X²R⁹ wherein X² is as defined above and R⁹ isaryl containing a total of 6 to 10 ring atoms, heteroaryl containing atotal of 5 to 10 ring atoms or unsaturated, partially unsaturated orsaturated carbocycloalkyl or heterocycloalkyl each containing a total of3 to 10 ring atoms, and R⁴ at each occurrence independently is hydrogen,(C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl, wherein each ring within A²and R⁸ contains from 3 to 8 ring atoms and may be substituted with 1 to3 groups independently selected from (C₁₋₆)alkyl, cyano, halo, nitro,halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶, —X²C(O)OR⁴,—X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴, —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴,—X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴, —X²NR⁴C(NR⁴)NR⁴R⁴, —X²C(O)NR⁴X²C(O)OR⁴,—X²NR²S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴, wherein X² and R⁴ are as defined aboveand R⁶ is (C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl, and wherein anysaid heterocycloalkylene, carbocycloalkyl and heterocycloalkyl ringswithin A² and R⁸ may be substituted further with 1 to 2 groupsindependently selected from (C₁₋₆)alkylidene, oxo, imino and thioxo; andA³ is a monocyclic or fused polycyclic ring system selected from arylcontaining a total of 6 to 14 ring atoms, heteroaryl containing a totalof 5 to 14 ring atoms and unsaturated, partially unsaturated orsaturated carbocycloalkyl or heterocycloalkyl each containing a total of3 to 14 ring atoms, wherein A³ may be substituted with a group selectedfrom —X²R^(9′), —X²OR^(9′), —X²C(O)R^(9′), —X²OC(O)R^(9′),—X²C(O)OR^(9′), —X²SR^(9′), —X²S(O)R^(9′), —X²S(O)₂R^(9′), —X²NR⁴R^(9′),—X²NR⁴C(O)R^(9′), —X²NR⁴C(O)OR^(9′), —X²C(O)NR⁴R^(9′),—X²NR⁴C(O)NR⁴R^(9′), —X²NR⁴C(NR⁴)NR⁴R^(9′), —X²NR⁴S(O)₂R^(9′) and—X²S(O)₂NR⁴R^(9′), wherein X² is a bond or (C₁₋₆)alkylene, R^(9′) is—X²R¹⁰ wherein X² is as defined above and R¹⁰ is aryl containing a totalof 6 to 10 ring atoms, heteroaryl containing a total of 5 to 10 ringatoms or unsaturated, partially unsaturated or saturated carbocycloalkylor heterocycloalkyl each containing a total of 3 to 10 ring atoms, andR⁴ at each occurrence independently is hydrogen, (C₁₋₆)alkyl orhalo-substituted (C₁₋₆)alkyl, wherein each ring within A³ and R¹⁰contains from 3 to 8 ring atoms and may be substituted with 1 to 3groups independently selected from (C₁₋₆)alkyl, cyano, halo, nitro,halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶, —X²C(O)OR⁴,—X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴, —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴,—C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴, —X²NR⁴C(NR⁴)NR⁴R⁴, —X²NR⁴S(O)₂R⁶ and—X²S(O)₂NR⁴R⁴, wherein X² and R⁴ are as defined above and R⁶ is(C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl, and wherein any saidcarbocycloalkyl and heterocycloalkyl rings within A³ and R¹⁰ may besubstituted further with 1 to 2 groups independently selected from(C₁₋₆)alkylidene, oxo, imino and thioxo, with the proviso that only oneof A³ and R¹⁰ is a fused polycyclic ring system; and the individualstereoisomers and mixtures of stereoisomers; and the pharmaceuticallyacceptable salts thereof; with the proviso that when said compound isFormulae II(a):

then A³ is other than: unsubstituted pyridyl; unsubstituted thienyl;unsubstituted indolyl; unsubstituted phenyl; benzo[1,3]dioxolyl;2,3-dihydro-benzo[1,4]dioxinyl; phenyl which is mono-substituted byfluoro, bromo, iodo, nitro, methyl, isopropyl, ethoxy or methylsulfanyl;and phenyl which is substituted by at least one of chloro, hydroxy ormethoxy.
 2. The compound of claim 1, and the individual stereoisomersand mixtures of stereoisomers; and the pharmaceutically acceptable saltsof said compound, with the further proviso that A³ is other than:unsubstituted pyridyl; unsubstituted thienyl; unsubstituted indolyl;unsubstituted phenyl; benzo[1,3]dioxolyl;2,3-dihydro-benzo[1,4]dioxinyl; and phenyl which is substituted by atleast one of halogen, nitro, hydroxy, (C₁₃)alkyl, methoxy, ethoxy andmethylsulfanyl.
 3. The compound of claim 1, and the individualstereoisomers and mixtures of stereoisomers; and the pharmaceuticallyacceptable salts of said compound, with the further proviso that A¹ isnot 4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl.
 4. The compound of claim 1in which said compound is of Formula I(A):

in which R¹, A¹, A² and A³ are as defined in claim 1; and the individualstereoisomers and mixtures of stercoisomers; and the pharmaceuticallyacceptable salts thereof.
 5. The compound of claim 4 in which saidcompound is of Formula I(B):

and the individual stereoisomers and mixtures of stereoisomers; and thepharmaceutically acceptable salts thereof.
 6. The compound of claim 5 inwhich said A² is 2,3,6,7-tetrahydro-[1,4]thiazepin-5,7-ylene, that isthe compound of Formula I(C):

in which said 2,3,6,7-tetrahydro-[1,4]thiazepin-5,7-ylene may besubstituted with 1 to 3 groups independently selected from (C₁₋₆)alkyl,cyano, halo, nitro, halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶,—X²OC(O)R⁶, —X²C(O)OR⁴, —X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴,—X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴, —X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴,—X²NR⁴C(NR⁴)NR⁴R⁴, —X²C(O)NR⁴X²C(O)OR⁴, —X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴,wherein X² is a bond or (C₁₋₆)alkylene, R⁴ at each occurrenceindependently is hydrogen, (C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl,and R⁶ is (C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl; and theindividual stereoisomers and mixtures of stereoisomers; and thepharmaceutically acceptable salts thereof.
 7. The compound of claim 6 inwhich A¹ is 4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; and the individual stereoisomersand mixtures of stereoisomers; and the pharmaceutically acceptable saltsthereof.
 8. The compound of claim 7 in which said compound is selectedfrom the group consisting of:4-hydroxy-6-methyl-3-[7-(3-phenyl-1H-pyrazol-4-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;3-[7-(5-ethyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;3-[7-(1-benzyl-1H-indol-3-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;4-hydroxy-6-methyl-3[7-(2-trifluoromethylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;4-hydroxy-6-methyl-3[7-(3-trifluoromethylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;4-hydroxy-6-methyl-3[7-(4-trifluoromethylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;4-hydroxy-6-methyl-3-[7-[3-(3-trifluoromethyl-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;3-[7-[3-(3,4-dichloro-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;3-[7-[3-(3,5-dichloro-phenoxy)-phenyl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;4-hydroxy-6-methyl-3-{7-[5-(3-trifluoromethyl-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-pyran-2-one;3-{7-[5-(2-chloro-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;3-{7-[5-(3-chloro-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;3-{7-[5-(4-chloro-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;4-hydroxy-6-methyl-3-{7-[5-(2-chloro-5-trifluoromethyl-phenyl)-furan-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-pyran-2-one;3-[7-(4-bromo-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;3-[7-(5-bromo-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;3-[7-(1-benzenesulfonyl-1H-pyrrol-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;4-hydroxy-6-methyl-3-[7-(3-methyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;4-hydroxy-6-methyl-3-[7-(5-methyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;4-hydroxy-6-methyl-3-[7-(1-methyl-1H-indol-3-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;3-[7-(3-chloro-2-methyl-5-trifluoromethyl-1H-pyrazol-4-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;3-{7-[1-(2,4-difluoro-benzenesulfonyl)-1H-pyrrol-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;3-(7-[2,2′]bithienyl-5-yl-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl)-4-hydroxy-6-methyl-pyran-2-one;3-{7-[1-(3,5-dichloro-phenyl)-1H-pyrrol-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;3-{7-[1-(4-chloro-phenyl)-1H-pyrrol-2-yl]-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl}-4-hydroxy-6-methyl-pyran-2-one;3-[7-(5-chloro-1H-indol-3-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;4-hydroxy-6-methyl-3-[7-(6-p-tolylsulfanyl-imidazo[2,1-b]thiazol-5-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;3-[7-(4,5-dibromo-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;4-hydroxy-6-methyl-3-[7-(5-methylsulfanyl-thien-2-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;3-[7-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-yl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;3-[7-(4-dimethylamino-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;4-hydroxy-6-methyl-3-[7-(4-trifluoromethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-pyran-2-one;3-[7-(bis-trifluoromethyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;4-hydroxy-3-[7-(4-methanesulfonyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one;and3-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-methoxy-6-methyl-pyran-2-one;and the pharmaceutically acceptable salts thereof.
 9. The compound ofclaim 6 in which A¹ is4-hydroxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl; and the individualstereoisomers and mixtures of stereoisomers; and the pharmaceuticallyacceptable salts thereof.
 10. The compound of claim 9 in which saidcompound is selected from the group consisting of:3-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one;3-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one;3-[7-(4-dimethylamino-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one;and3-[7-(2,3,4-trimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one;and the pharmaceutically acceptable salts thereof.
 11. The compound ofclaim 6 in which A¹ is 2-hydroxy-6-oxo-cyclohex-1-enyl or2-methoxy-6-oxo-cyclohex-1-enyl; and the individual stereoisomers andmixtures of stereoisomers; and the pharmaceutically acceptable saltsthereof.
 12. The compound of claim 11 in which said compound is selectedfrom the group consisting of:2-[7-(2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-3-hydroxy-cyclohex-2-enone;2-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-3-hydroxy-cyclohex-2-enone; and3-hydroxy-2-[7-(2,3,4-trimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-cyclohex-2-enone;and the pharmaceutically acceptable salts thereof.
 13. The compound ofclaim 6 in which A¹ is a group of Formula (c):

in which R⁷ is hydrogen or methyl, R¹¹ is hydrogen or (C₁₋₆)alkyl andthe free valence is attached to A²; and the individual stereoisomers andmixtures of stereoisomers; and the pharmaceutically acceptable saltsthereof.
 14. The compound of claim 13 which is:3-[7-2,4-dimethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-1H-quinolin-2-one;and the pharmaceutically acceptable salts thereof.
 15. The compound ofclaim 4 in which said A² is a group of Formula (k):

in which said group of Formula (k) may be substituted with 1 to 3 groupsindependently selected from (C₁₋₆)alkyl, cyano, halo, nitro,halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶, —X²C(O)OR⁴,—X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴, —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴,—X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴, —X²NR⁴C(NR⁴)NR⁴R⁴,—X²C(O)NR⁴X²C(O)OR⁴, —X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴, wherein X² is abond or (C₁₋₆)alkylene, R⁴ at each occurrence independently is hydrogen,(C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl, and R⁶ is (C₁₋₆)alkyl orhalo-substituted (C₁₋₆)alkyl; and the individual stereoisomers andmixtures of stereoisomers; and the pharmaceutically acceptable saltsthereof.
 16. The compound of claim 15 in which R¹ is hydrogen; and theindividual stereoisomers and mixtures of stereoisomers; and thepharmaceutically acceptable salts thereof.
 17. The compound of claim 15in which A¹ is 4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; and the individual stereoisomersand mixtures of stereoisomers; and the pharmaceutically acceptable saltsthereof.
 18. The compound of claim 17 in which said compound is selectedfrom the group consisting of:3-[4-acetyl-7-(2,4-dimethoxy-phenyl)-[1,4]thiazepan-5-yl]-4-hydroxy-6-methyl-pyran-2-one; and3-[7-(2,4-dimethoxy-phenyl)-4-(2,2,2-trifluoro-ethanoyl)-[1,4]thiazepan-5-yl]-4-hydroxy-6-methyl-pyran-2-one;and the pharmaceutically acceptable salts thereof.
 19. The compound ofclaim 15 in which A¹ is optionally substituted phenyl.
 20. The compoundof claim 19 which is:1-[7-(2,4-dimethoxy-phenyl)-5-(3-fluoro-4-methoxyphenyl)-[1,4]thiazepan-4-yl]-ethanone;and the pharmaceutically acceptable salts thereof.
 21. The compound ofclaim 4 in which said A² is 2,3-dihydro-[1,4]thiazepin-5,7-ylene that isthe compound of Formula I(F):

in which said 2,3-dihydro-[1,4]thiazepin-5,7-ylene may be substitutedwith 1 to 3 groups independently selected from (C₁₋₆)alkyl, cyano, halo,nitro, halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶,—X²C(O)OR⁴, —X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴, —X²NR⁴C(O)R⁶,—X²NR⁴C(O)OR⁴, —X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴, —X²NR⁴C(NR⁴)NR⁴R⁴,—X²C(O)NR⁴X²C(O)OR⁴, —X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴, wherein X² is abond or (C₁₋₆)alkylene, R⁴ at each occurrence independently is hydrogen,(C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl, and R⁶ is (C₁₋₆)alkyl orhalo-substituted (C₁₋₆)alkyl; and the individual stereoisomers andmixtures of stereoisomers; and the pharmaceutically acceptable saltsthereof.
 22. The compound of claim 21 in which A¹ is4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; and the individual stereoisomersand mixtures of stereoisomers; and the pharmaceutically acceptable saltsthereof.
 23. The compound of claim 22 in which said compound is selectedfrom the group consisting of:3-[7-(2,4-dimethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;3-[7-(2,4-diethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one; and3-(7-[2,2′]bithienyl-5-yl-2,3-dihydro-[1,4]thiazepin-5-yl)-4-hydroxy-6-methyl-pyran-2-one;and the pharmaceutically acceptable salts thereof.
 24. The compound ofclaim 21 in which A¹ is4-hydroxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl; and the individualstereoisomers and mixtures of stereoisomers; and the pharmaceuticallyacceptable salts thereof.
 25. The compound of claim 24 which is:3-[7-(2,4-diethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one; and the pharmaceutically acceptable saltsthereof.
 26. The compound of claim 26 in which A¹ is2-hydroxy-6-oxo-cyclohex-1-enyl or 2-methoxy-6-oxo-cyclohex-1-enyl; andthe individual stereoisomers and mixtures of stereoisomers; and thepharmaceutically acceptable salts thereof.
 27. The compound of claim 26which is:2-[7-(2,4-diethoxy-phenyl)-2,3-dihydro-[1,4]thiazepin-5-yl]-3-hydroxy-cyclohex-2-enone;and the individual stereoisomers and mixtures of stereoisomers; and thepharmaceutically acceptable salts thereof.
 28. The compound of claim 1in which said compound is of Formula I(G):

in which n, R¹, A¹, A² and A³ are defined as in claim 1; and theindividual stereoisomers and mixtures of stereoisomers; and thepharmaceutically acceptable salts thereof.
 29. The compound of claim 28in which A² is a group of Formula (1):

in which said group of Formula (1) may be substituted with 1 to 3 groupsindependently selected from (C₁₋₆)alkyl, cyano, halo, nitro,halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²C(O)R⁶, —X²OC(O)R⁶, —X²C(O)OR⁴,—X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶, —X²NR⁴R⁴, —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴,—X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴, —X²NR⁴C(NR⁴)NR⁴R⁴, —X²C(O)NR⁴X²C(O)OR⁴,—X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴, wherein X² is a bond or (C₁₋₆)alkylene,R⁴ at each occurrence independently is hydrogen, (C₁₋₆)alkyl orhalo-substituted (C₁₋₆)alkyl, and R⁶ is (C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl; and the individual stereoisomers and mixtures ofstereoisomers; and the pharmaceutically acceptable salts thereof. 30.The compound of claim 29 in which n is 1 and A¹ is4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; and the individual stereoisomersand mixtures of stereoisomers; and the pharmaceutically acceptable saltsthereof.
 31. The compound of claim 30 which is:3-[7-(2,4-dimethoxy-phenyl)-1-oxo-2,3,6,7-tetrahydro-1H-1λ⁴-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;and the pharmaceutically acceptable salts thereof.
 32. The compound ofclaim 29 in which n is 2 and A¹ is4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl or4-methoxy-6-methyl-2-oxo-2H-pyran-3-yl; and the individual stereoisomersand mixtures of stereoisomers; and the pharmaceutically acceptable saltsthereof.
 33. The compound of claim 32 which is:3-[7-(2,4-dimethoxy-phenyl)-1,1-dioxo-2,3,6,7-tetrahydro-1H-1λ⁶-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;and the individual stereoisomers and mixtures of stereoisomers; and thepharmaceutically acceptable salts thereof.
 34. A compound selected fromthe group consisting of:4-hydroxy-3-[7-(2-methoxy-4-methylsulfanyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one;3-[7-(2-chloro-5-trifluoromethyl-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;3-[7-(4-dimethylamino-2-methoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one;4-hydroxy-3-[7-(4-chloro-2-methoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one;and4-hydroxy-3-[7-(2,4-diethoxy-phenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-6-methyl-pyran-2-one;or an individual stereoisomer and mixtures of stereoisomers; or thepharmaceutically acceptable salt thereof.
 35. A compound selected fromthe group consisting of:7-(2,4-dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepine-3-carboxylicacid; and2-({1-[7-(2,4-dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepin-3-yl]-methanoyl}-amino)-propionicacid tert-butyl ester; and the pharmaceutically acceptable saltsthereof.
 36. The compound of claim 1 in which A¹ is a group selectedfrom Formulae (b), (c), (d), (e) and (f):

in which R⁷ is hydrogen or methyl, R¹¹ is hydrogen or (C₁₋₆)alkyl andthe free valance is attached to A²; and A² is as defined in claim 1 oris a monocyclic ring from heteroarylene or unsaturated, partiallyunsaturated or saturated heterocycloalkylene containing a total of 7ring atoms, wherein A²may be substituted with a group selected from—X²R⁸, —X²OR⁸, —X²C(O)R⁸, —X²OC(O)R⁸, —X²C(O)OR⁸, —X²SR⁸, —X²S(O)R⁸,—X²S(O)₂R⁸, —X²NR⁴R⁸, —X²NR⁴C(O)R⁸, —X²NR⁴C(O)OR⁸, —X²C(O)NR⁴R⁸,—X²NR⁴C(O)NR⁴R⁸, —X²NR⁴C(NR⁴)NR⁴R⁸, —X²NR⁴S(O)₂R⁸ and —X²S(O)₂NR⁴R⁸,wherein X² is a bond or (C₁₋₆)alkylene, R⁸ is —X²R⁹ wherein X² is asdefined above and R⁹ is aryl containing a total of 6 to 10 ring atoms,heteroaryl containing a total of 5 to 10 ring atoms or unsaturated,partially unsaturated or saturated carbocycloalkyl or heterocycloalkyleach containing a total of 3 to 10 ring atoms, and R⁴ at each occurrenceindependently is hydrogen, (C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl,wherein each ring within A² and R⁸ that contains from 3 to 8 ring atomsand may be substituted with 1 to 3 groups independently selected from(C₁₋₆)alkyl, cyano, halo, nitro, halo-substituted (C₁₋₆)alkyl, —X²OR⁴,—X²C(O)R⁶, —X²OC(O)R⁶, —X²C(O)OR⁴, —X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶,—X²NR⁴R⁴, —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁶, —X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴,—X²NR⁴C(NR⁴)NR⁴R⁴, —X²C(O)NR⁴X²C(O)OR⁴, —X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴,wherein X² and R⁴ are as defined above and R⁶ is (C₁₋₆)alkyl orhalo-substituted (C₁₋₆)alkyl, and wherein any said heteroalkylene,carbocycloalkyl and heterocycloalkyl rings within A² and R⁸ may besubstituted further with 1 to 2 groups independently selected from(C₁₋₆)alkylidene, oxo, imino and thioxo; and the individualstereoisomers and mixtures of stereoisomers; and the pharmaceuticallyacceptable salts thereof.
 37. The compound of claim 36 in which A² is agroup selected from Formulae (h), (i), (j), (k), (l) and (m):

in which n is 1 or 2 and R¹ is acetyl or trifluoroacetyl; and theindividual stereoisomers and mixtures of stereoisomers; and thepharmaceutically acceptable salts thereof.
 38. A compound of Formula II:

in which: the dashed lines indicate optional unsaturation withoutviolating valency rules; R¹ is hydrogen, (C₁₋₆)alkyl or —C(O)R⁶, whereinR⁶ is as defined below, or R¹ is absent when a double bond existsbetween the nitrogen atom to which R¹ is attached and an adjacent ringatom; R⁷ is hydrogen; X¹ is —S(O)_(n)—, wherein n is 0, 1, or 2; A² is amonocyclic ring selected from heteroarylene or unsaturated, partiallyunsaturated or saturated heterocycloalkylene containing a total of 7ring atoms, wherein A² may be substituted with a group selected from—R⁸, —X²OR⁸, —X²C(O)R⁸, —X²OC(O)R⁸, —X²C(O)OR⁸, —X²SR⁸, —X²S(O)R⁸,—X²S(O)₂R⁸, —X²NR⁴R⁸, —X²NR⁴C(O)R⁸, —X²NR⁴C(O)OR⁸,—X²C(O)NR⁴R⁸,—X²NR⁴C(O)NR⁴R⁸, —X²NR⁴C(NR⁴)NR⁴R⁸, —X²NR⁴S(O)₂R⁸ and —X²S(O)₂NR⁴R⁸,wherein X² is a bond or (C₁₋₆)alkylene, R⁸ is —X²R⁹ wherein X² is asdefined above and R⁹ is aryl containing a total of 6 to 10 ring atoms,heteroaryl containing a total of 5 to 10 ring atoms or unsaturated,partially unsaturated or saturated carbocycloalkyl or heterocycloalkyleach containing a total of 3 to 10 ring atoms, and R⁴ at each occurrenceindependently is hydrogen, (C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl,wherein each ring within A² and R⁸ contains from 3 to 8 ring atoms andmay be substituted with 1 to 3 groups independently selected from(C₁₋₆)alkyl, cyano, halo, nitro, halo-substituted (C₁₋₆)alkyl, —X²OR⁴,—X²C(O)R⁶, —X²OC(O)R⁶, —X²C(O)OR⁴, —X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶,—X²NR⁴R⁴, —X²NR⁴C(O)R⁶, —X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴,—X²NR⁴C(NR⁴)NR⁴R⁴, —X²C(O)NR⁴X²C(O)OR⁴, —X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴,wherein X² and R⁴ are as defined above and R⁶ is (C₁₋₆)alkyl orhalo-substituted (C₁₋₆)alkyl, and wherein any said heteroalkylene,carbocycloalkyl and heterocycloalkyl rings within A² and R⁸ may besubstituted further with 1 to 2 groups independently selected from(C₁₋₆)alkylidene, oxo, imino and thioxo; and A³ is a monocyclic or fusedpolycyclic ring system selected from aryl containing a total of 6 to 14ring atoms, heteroaryl containing a total of 5 to 14 ring atoms andunsaturated, partially unsaturated or saturated carbocycloalkyl orheterocycloalkyl each containing a total of 3 to 14 ring atoms, whereinA³ may be substituted with a group selected from —²R^(9′), —X²OR^(9′),—X²C(O)R^(9′), —X²OC(O)R^(9′), —X²C(O)OR^(9′), —X²SR^(9′),—X²S(O)R^(9′), —X²S(O)₂R^(9′), —X²NR⁴R^(9′), —X²NR⁴C(O)R^(9′),—X²NR⁴C(O)OR^(9′), —X²C(O)NR⁴R^(9′), —X²NR⁴C(O)NR⁴R^(9′),—X²NR⁴C(NR⁴)NR⁴R^(9′), —X²NR⁴S(O)₂R⁹ and —X²S(O)₂NR⁴R⁹, wherein X² is abond or (C₁₋₆)alkylene, R^(9′) is —X²R¹⁰ wherein X² is as defined aboveand R¹⁰ is aryl containing a total of 6 to 10 ring atoms, heteroarylcontaining a total of 5 to 10 ring atoms or unsaturated, partiallyunsaturated or saturated carbocycloalkyl or heterocycloalkyl eachcontaining a total of 3 to 10 ring atoms, and R⁴ at each occurrenceindependently is hydrogen, (C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl,wherein each ring within A³ and R¹⁰ contains from 3 to 8 ring atoms andmay be substituted with 1 to 3 groups independently selected from(C₁₋₆)alkyl, cyano, halo, nitro, halo-substituted (C₁₋₆)alkyl, —X²OR⁴,—X²C(O)R⁶, —X²OC(O)R⁶, —X²C(O)OR⁴, —X²SR⁴, —X²S(O)R⁶, —X²S(O)₂R⁶,—X²NR⁴R⁴, —X²NR⁴C(O)R⁶, —X²NR⁴C(O)OR⁴, —X²C(O)NR⁴R⁴, —X²NR⁴C(O)NR⁴R⁴,—X²NR⁴C(NR⁴)NR⁴R⁴, —X²NR⁴S(O)₂R⁶ and —X²S(O)₂NR⁴R⁴, wherein X² and R⁴are as defined above and R⁶ is (C₁₋₆)alkyl or halo-substituted(C₁₋₆)alkyl, and wherein any said carbocycloalkyl and heterocycloalkylrings within A³ and R¹⁰ may be substituted further with 1 to 2 groupsindependently selected from (C₁₋₆)alkylidene, oxo, imino and thioxo withthe proviso that only one of A³ and R¹⁰ is a fused polycyclic ringsystem; and the individual stereoisomers and mixtures of stereoisomers;and the pharmaceutically acceptable salts thereof; provided, however,Formula II does not represent a compound wherein A² is2,3,6,7-tetrahydro-[1,4]thiazepinylene and A³ is benzo[1,3]dioxolyl,indolyl, phenyl, pyridyl or thienyl, wherein said phenyl may besubstituted with 1 to 3 groups independently selected from halo, nitro,hydroxy, (C₁₋₄)alkyl, (C₁₋₄)alkylsulfanyl and (C₁₋₄)alkyloxy or anyindividual stereoisomer or mixture of stereoisomers, or pharmaceuticallyacceptable salt thereof.
 39. The compound of claim 38 in which A² is agroup selected from Formulae (h), (k), (l) and (m):

in which n is 1 or 2 and R¹ is acetyl or trifluoroacetyl; and theindividual stereoisomers and mixtures of stereoisomers; and thepharmaceutically acceptable salts thereof.
 40. The compound of claim 39in which A³ is phenyl or heteroaryl containing a total of 5 to 9 ringatoms, wherein A³ may be substituted with a group selected from —R^(9′),—X²OR^(9′), —X²SR^(9′) and —X²S(O)₂R^(9′), wherein R^(9′) is —X²R¹⁰, X²is a bond or (C₁₋₆)alkylene and R¹⁰ is phenyl or heteroaryl containing atotal 5 to 6 ring atoms, wherein each ring within A³ and R¹⁰ may besubstituted with 1 to 3 groups independently selected from (C₁₋₆)alkyl,halo, halo-substituted (C₁₋₆)alkyl, —X²OR⁴, —X²SR⁴, —X²S(O)₂R⁶ and—X²NR⁴R⁴, wherein R⁴ at each occurrence independently is hydrogen,(C₁₋₆)alkyl or halo-substituted (C₁₋₆)alkyl and R⁶ is (C₁₋₆)alkyl orhalo-substituted (C₁₋₆)alkyl; and the individual stereoisomers andmixtures of stereoisomers; and the pharmaceutically acceptable saltsthereof.